Dosage form for insertion into the mouth

ABSTRACT

Oral dosage forms as a biodegradable, water soluble film for delivering pharmaceutically active agents, to patients through insertion into the mouth of patient and methods for administering pharmaceutically active agents to patients by insertion into the mouth to provide selective uptake of said agents through the mucosa and thus avoiding the gastrointestinal tract.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/655,194, filed Oct. 18, 2012 which is a divisional of U.S. patentapplication Ser. No. 12/608,445 filed Oct. 29, 2009, which claims thebenefit of priority of U.S. Provisional Application No. 61/110,775 filedon Nov. 3, 2008, the contents of each of which are hereby incorporatedby reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to oral dosage forms for insertion intothe mouth for selective adsorption by the mucosal tissue, particularlyfor administration of medicinal agents where fast onset of action isdesirable medicines such as but not limited to anti-migraine agents. Inparticular, the present invention relates to pharmaceutical formulationof the anti-migraine drugs in the class of triptans.

BACKGROUND OF THE INVENTION

Migraine is one of the most common neurological conditions. Migraineheadaches affect a large portion of the U.S. population and are moreprevalent than diabetes, epilepsy and asthma combined. Migraine is morethan just a headache. It can be a debilitating condition which has aconsiderable impact on the quality of life of sufferers and theirfamilies. Attacks can be completely disabling, forcing the sufferer toabandon everyday activities. Even in symptom-free periods, sufferers maylive in fear of the next attack. Migraine attacks normally last between4 and 72 hours and sufferers are usually symptom free between attacks.

Migraine is believed to be caused by the release of a chemical calledserotonin or 5HT into the bloodstream. This causes the pain neurons inthe blood vessel wall to become irritated. Exactly what causes therelease of serotonin is still a subject for research and debate.However, certain factors have been identified which can trigger attacksin susceptible people. Some of these are stress or sometimes the reliefof stress, lack of food or infrequent meals, foods containingingredients such as mono-sodium glutamate, caffeine and chocolate, oralcohol (especially red wine), overtiredness (physical or mental),changes in sleep patterns (e.g., late nights or a weekend lie-in), orhormonal factors (e.g., monthly periods, the contraceptive pill orhormonal changes in males and females as they age).

Migraines are more common than cluster headaches, and have been studiedmore extensively. In addition, a better and more effective set of drugshave been developed to treat migraines, than cluster headache. For thosereasons, the discussion below focuses mainly on migraines, rather thancluster headaches.

“Cluster headaches” were given that name because they tend to occur inepisodic clusters, with a cluster cycle usually lasting 4 to 8 weeks. Insome patients, a cluster occurs only once in a lifetime; in otherpatients, a cluster may occur roughly once a year, pith periods ofcomplete remission between attacks; and, in the roughly 10% of patientswho are chronic sufferers, there are no significant periods ofremission. As opposed to migraines (which occur in women at roughly 3times the rates as in men), cluster headaches are more prevalent in menthan in women, by a factor of about 5:1 or higher.

Migraines and cluster headaches are both classified as “recurrentprimary headaches”. They are recurrent, since they recur with sufficientfrequency to seriously interfere with the health and quality of life ofa patient, to a point of requiring and demanding medical attention, asopposed to just taking aspirin or similar over-the-counter analgesicsand lying down till it passes. They are also regarded as “primary”headaches, since they usually arise as a primary adverse biologiccondition, independently of other causative medical conditions such astumors, sinus or other infections, bleeding problems, etc.

Current methods for administering anti-migraine pharmaceuticals havemajor limitations. For example, due to degradation in thegastrointestinal track and low adsorption of the drug, oral ingestibledosage forms of anti-migraine medications have to be administered inlarge doses of about 20-100 mg. These high doses may causes nausea,vomiting and other unwanted adverse side effects. Many anti-migraineagents are subject to pre-systemic and first pass metabolism. Because ofthis, it is estimated that as little as 2-10% of the active unchangeddrug actually reaches the blood stream. In fact this causes delay in theeffectiveness of the drug as a treatment or prophylaxis of the disorderin the patient. Likewise, intranasal administration of anti-migraineagents is hampered with significant limitations due to reducedabsorption and low bioavailability.

Injectable and nasal spray forms of anti-migraine agents are alsoavailable for the treatment of migraines. Although parenteraladministration of anti-migraine agents into the blood stream allows fora lower dose as compared to other non-injectable methods ofadministration, the inconvenience of an office visit for an injection orproblems with the self-administration of injectables are self evident.

In the past, migraine headaches have been treated by use ofrizaptriptan, sumatriptan, zolmitriptan or other triptan drugs. Thesedrugs have basically been administered using conventional dosage formssuch as pills or capsules or for sumatriptan through injection and nasalspray. The problem with the gastrointestinal (GI) administered triptananti-migraine pharmaceutical agents is that they have a low GIbioavailability of approximately 15% to 40% and cause GI irritations. Inaddition, it is important that these drugs be delivered rapidly to apatient to prevent or treat the onset of a migraine headache and giveimmediate relief. The delay in release of the drug from the dosage forminto and the bioavailability of the drug after administration causesundue suffering in the patient which is especially acute with patientssuffering from migraine headaches. Therefore, what is needed areformulations that are effective for treating migraines which allow rapiddrug release and bioavailability while avoiding the GI irritations whichoccur with the known administration of anti-migraine medications.

Triptans have been developed for the acute treatment of migraine. Thesemedicines are available in the form of tablets for eletriptan,frovatriptan, sumatriptan, zolmitriptan, naratriptan, rizatriptan andalmotriptan. These products are intended to be taken in amounts up to amaximum of 5 to 200 mg per day. Table A summarizes dosing regimens fortriptan products.

TABLE A Triptan Dosing Regimens Maximum 24 Generic Name Dose Brand Namehour Dose Almotriptan 12.5 mg Axert 12.5 mg Eletriptan 40 mg Relpax 80mg Frovatriptan 2.5 mg Frova 7.5 mg Naratriptan 2.5 mg Amerge 5.0 mgRizatriptan 10 mg Maxalt 30 mg Sumatriptan 100 mg Imitrex 200 mgSumatriptan 6 mg Imitrex 6 mg injection Sumatriptan 20 mg Imitrex 40 mgnasal spray Zolmitriptan 2.5 mg Zomig 10 mg Zolmitriptan 5 mg Zomig ZMT10 mg Zolmitriptan 5 mg Zomig ZMT 10 mg Oral form unless otherwisenoted.

SUMMARY OF INVENTION

We have discovered a water soluble matrix which can be incorporated intoa solid, film or liquid oral dosage form for insertion into the mouth asa means for effectively delivering to, and transporting pharmaceuticalactive agents selectively through the oral mucosal tissue into thepatient. This water soluble matrix system delivers the pharmaceuticalactive agent effectively and rapidly into the body through the mucousmembranes in the mouth. While this system is effective for deliveringpharmaceutically active agents, this system is ideally suited fordelivering pharmaceutically active agents which treat or preventmigraine headaches, especially the triptans which include eletriptan,frovatriptan, sumatriptan, zolmitriptan, naratriptan, rizatriptan andalmotriptan. Preferred triptans for selective oral mucosal delivery arerizaptriptan, sumatriptan and zolmitriptan.

The oral dosage matrix of this invention transports thesepharmaceutically active agents selectively through the mucous membranein the mouth bypassing the GI system so as to avoid GI irritations anddeactivation of the active agent in the GI track. Without GIinactivation, less active agent is needed to produce a therapeuticresult. In addition, the oral dosage matrix of this invention rapidlyreleases the pharmaceutically active agent for transport quickly intothe blood stream of the patient. Transport of the active agentsselectively through the mucus membranes of the mouth is facilitated byincorporating one or more fatty acid esters of sucrose having a combinedhydrophilic lipophilic balance (HLB) of about 8 to about 16 with theactive agent to form the matrix. The fatty acid esters of sucrose are aneffective absorption enhancer. The oral dosage matrix of this inventionproduces improved bioavailability and delivery of the pharmaceuticalactive agent with rapid onset of therapeutic effectiveness for thepatient. Rapid release and rapid, efficient absorption is particularlyimportant for patients suffering from migraine headaches.

The oral dosage matrix, pharmaceutically active agent and fatty acidester of sucrose, may be added to additional ingredients to producedosage forms such as a film, a rapid releasing solid such as a powder orgranule, a tablet, and also a liquid which contain an effective amountof the pharmaceutically active agent to relieve a migraine and relatedsymptoms or act as a prophylactic disbursed therein. In accordance withthis invention, this oral dosage matrix when incorporated into a tablet,film or other solid dosage form or solid dosage unit may furthercomprise a polymeric mixture of polyvinyl pyrrolidone and a polymericalginate. This solid dosage form is of a size suitable for insertioninto the mouth. In particular, this solid dosage form is particularlyadvantageous for administration of anti migraine agents which function,either or both, as a prophylactic and a treatment of migraine headaches.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 graphs the plasma levels versus time after administrationresulting from three liquid dosage forms not containing absorptionenhancers with different dosage amounts of rizatriptan.

FIG. 2 graphs the plasma levels versus time of rizatriptan afteradministration resulting from three liquid dosage forms containing thesame amount of rizatriptan and absorption enhancers compared with aliquid dosage form containing the same amount of rizatriptan and notcontaining absorption enhancers.

FIG. 3 graphs the plasma levels of rizatriptan versus time afteradministration of formulations Examples 29 to 34.

DETAILED DESCRIPTION

In accordance with this invention, a new delivery matrix is provided foradministering pharmaceutically active agents (also known as activecompounds) to a patient by means of selective absorption through mucousmembranes located in the mouth. Absorption is the movement of drug intothe blood stream. This invention constitutes a matrix which can beincorporated into new oral dosage forms such as a film or tablet and aliquid dosage form. The term oral dosage form shall include but not belimited to an oral disintegrating tablet, paste, gel, liquid, emulsion,film, lollipop, lozenge, buccal and gingival patch, granule and powdereddosage forms. The terms dosage form or dosage unit shall mean thecombination of the matrix, which comprises a pharmaceutical active agentand one or more fatty acid esters of sucrose having a combined HLB ofabout 8 to about 16, preferably about 9 to about 16, with additionalingredients to form a tablet, paste, gel, liquid, emulsion, film,lollipop, lozenge, buccal and gingival patch, granule and powdereddosage form for insertion into the mouth of a patient. The dosage formsare preferably water soluble. The dosage form contains an effectiveamount of the pharmaceutically active agent distributed therein. Thedosage form may optionally contain a polymeric mixture of polyvinylpyrrolidone and a polymeric alginate. When the dosage form is a solid itmay be contoured to a size suitable for insertion into the mouth.Preferred solid dosage forms are a film (ODF) and a tablet (ODT).Insertion into the mouth preferably occurs by sublingual or buccalinsertion which allows the pharmaceutical agent to be delivered to thepatient selectively through the mucosa in the mouth thereby bypassingthe GI system and allowing effective administration of pharmaceuticalactive agents that generally cause GI irritation or are renderedinactive in the GI system. Anti-migraine agents in the chemical classtriptans are known to cause GI irritation and are also known to berendered at least partially inactive by GI exposure. In some instances,the dosage form is placed on to the tongue where absorption may alsotake place. The dosage forms of this invention act as a carrier deviceto transmit the pharmaceutically active agents to a patient in a fastand effective manner. Preferably, the liquid dosage form will be placedunder the tongue for sublingual absorption. When only pharmaceuticallyactive agent and fatty acid ester of sucrose are present in the liquid,then the matrix is the dosage form.

This invention also is directed to a process for mitigating migraineheadaches, cluster headaches and related symptoms of migraine andcluster headaches in a patient by administering the oral unit dosageform into the mouth of the patient. Typical migraine symptoms arepainful headaches that can be one-sided and pulsating, lasting 4 to 72hours. Accompanying complaints are nausea and vomiting, and a heightenedsensitivity to bright lights (photophobia) and noise (hyperacusis).Approximately one third of people who experience migraines get apreceding aura, in which a patient may sense a strange light orunpleasant smell.

In one embodiment, of the present invention, the pharmaceutically activeagent is an anti-migraine agent. The preferred anti-migraine agents aretriptans selected from the group consisting of eletriptan, frovatriptan,sumatriptan, zolmitriptan, naratriptan, rizatriptan and almotriptan orpharmaceutically acceptable salts thereof. Suitable pharmaceuticallyacceptable salts of the active agents used in the dosage forms of thisinvention include acid addition salts which may, for example, be formedby mixing a solution of the pharmaceutically active agent according tothe invention with a solution of a pharmaceutically acceptable non-toxicacid such as hydrochloric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaricacid, carbonic acid or phosphoric acid. These anti-migraine agents arepresent in the dosage form in an amount effective for combating migraineby either treating the migraine headache and related symptoms orpreventing the onset of the migraine headache and related symptoms. Byinsertion of this dosage form into the mouth of the patient, thepharmaceutical agent is delivered by selective absorption through thepatient's oral mucosa tissue. In another embodiment of the presentinvention, the dosage form is placed on the tongue. In anotherembodiment of the present invention, a liquid matrix is placed in themouth of the patient and held there until the active agent has beenabsorbed. Absorption may take from about 0.5 minute to about 15 minutespreferably about 1 minute to about 10 minutes and more preferably 1minute to about 5 minutes. Placing the liquid dosage form into thepatient's mouth under the tongue is preferred. Liquid dosage forms maybe applied by spraying into the mouth from suitable spray device orplaced into the mouth with an eye dropper, pipette or similar device.Applicators are well known in the art. Dosing by film, tablet or liquidis preferably once or twice daily. Dosing may vary according to the ageof the patient, severity of the condition and the particular activeagent.

When the pharmaceutical agent is a triptan, the triptan is present inthe dosage form in the amount of from about 1 mg to about 100 mg as thebase. When the pharmaceutical agent is almotriptan it is present in anamount of about 2.5 to about 15 mg as the base. When the pharmaceuticalagent is rizatriptan it is present in an amount of about 2.5 to about 15mg as the base. When the pharmaceutical agent is naratriptan it ispresent in an amount of about 1 to about 5 mg as the base. When thepharmaceutical agent is zolmitriptan it is present in an amount of about1 to about 7.5 mg as the base. When the pharmaceutical agent issumatriptan it is present in an amount of about 3 to about 100 mg as thebase. Preferably, sumatriptan is present from about 3 to about 50 mg asthe base and more preferably from about 3 to about 25 mg as the base.When the pharmaceutical agent is frovatriptan it is present in an amountof about 1 to about 5 mg as the base. When the pharmaceutical agent iseletriptan it is present in an amount of about 10 to about 30 mg as thebase.

The term “triptan” as used herein includes compounds designed around anindole ring, with neurotropic activity in suppression of migraine pain.These include the free base form of this compound and its salts of thiscompound as well as all pharmacologically acceptable analogs,derivatives, and chemically modified forms, including acid additionsalts, thereof. In addition to chloride, other acceptable salts are thebromide, the iodide, the sulfuric, the phosphate, the acid phosphate,the lactate, the citrate, the tartarate, the salicylate, the succinate,the maleate, the gluconate, mesylate, and the like. Also included arefatty acid salts of the form “lipophilic ion pairs”, such as thelaurate, dodecylate, myristate, palmitate, stearate, coconoate,behinate, oleate, linoleate, linolenate, eicosapentaenoate,eicosahexaenoate, docosapentaenoate, docosahexaenoate, and eicosanoidsin general. Additional suitable pharmaceutically acceptable salts of thecompounds of this invention include acid addition salts which may, forexample, be formed by mixing a solution of the compound according to theinvention with a solution of a pharmaceutically acceptable non-toxicacid such as hydrochloric acid, fumaric acid, acetic acid, benzoic acid,oxalic acid, carbonic acid or phosphoric acid. Preferredpharmaceutically acceptable salts of rizatriptan are oxalate, succinate,hydrochloride and benzoate salts. In the treatment of migraine, asuitable dosage level for the rizatriptan or its pharmaceuticallyacceptable salts is from about 0.05 to 5 mg per kg as the base per day.In general with respect to rizatriptan, the film which forms the unitdosage form contains an amount of rizatriptan or its pharmaceuticallyacceptable salts, with amounts of from about 1 mg to about 25 mg as thebase with about 2 mg to about 20 mg as the base being preferred andabout 2.5 to about 15 mg as the base being most preferred. Generallythis unit dose will vary depending upon the size and weight of thepatient and the amount desired by the physician to be effective fortreating and/or preventing the onset of migraine headaches.

In a preferred embodiment of the present invention the dosage form is awater soluble film comprising the matrix and a polymeric mixture ofpolyvinyl pyrrolidone and a polymeric alginate. Preferably the filmcontains from about 5% to about 95% by weight of polyvinyl pyrrolidoneand from about 5% to about 95% of the polymeric alginate, both weightsbeing based upon the weight of the film. This film is formed from anaqueous mixture containing from about 5% to about 95% by weight ofpolyvinyl pyrrolidone and from about 5% to about 95% of the alginatesalt, both weights being based upon the dry weight of the mixture. Thealginate salt can be any conventional pharmaceutically acceptable salt,preferably the alkali earth metal salts and more preferably sodiumalginate. Both the polyvinyl pyrrolidone and a polymeric alginateutilized in forming this film are water soluble. Sufficient water isused in the formation of the aqueous mixture to dissolve the polyvinylpyrrolidone and alginate salt.

The polyvinyl pyrrolidone which is utilized in forming the film has amolecular weight of from about 1×10³ to about 1×10⁸ daltons and thepolymeric alginate has a molecular weight of from about 1×10³ to about1×10⁷ daltons and a viscosity of from about 400 cps to about 900 cpsmeasured in a 1% by weight aqueous solution.

In a preferred embodiment of the present invention the dosage form is awater soluble film comprising the matrix and pullulan. Pullulantypically has a molecular weight of about 5,000 to about 5,000,000daltons and preferably pullulan has a molecular weight of about 10,000to about 800,000 daltons.

The film oral solid dosage unit has a surface area of from about 0.25cm² to about 20 cm² and a weight of about 1 mg to about 200 mg,preferably from about 1 cm² to about 10 cm² and a weight of about 10 mgto about 500 mg, preferably about 10 mg to about 250 mg. The dry filmhas a thickness of between about 0.01 mm to about 5 mm, preferablybetween about 0.05 mm to about 2.5 mm. The film will dissolve in theoral cavity in about 0.25 minutes to about 15 minutes, preferably inabout 0.5 minutes to about 10 minutes. When the pharmaceuticalcomposition is a the tablet, when the placed in the oral cavity it willdissolve in about 0.25 minutes to about 15 minutes.

When the pharmaceutical composition is a film and said film preferablycontains one or more absorption enhancers in an amount of from about0.1% by weight to about 15% by weight of the film, more preferable, saidfilm contains a absorption enhancer in an amount of from about 1% byweight to about 10% by weight of the film.

When the pharmaceutical composition is a tablet said tablet preferablycontains a absorption enhancer in an amount of from about 0.1% by weightto about 20% by weight of the tablet, more preferably said tabletcontains a absorption enhancer in an amount of from about 1% by weightto about 15% by weight of the tablet.

When the pharmaceutical composition is a liquid contains a absorptionenhancer in an amount of from about 0.1% by weight to about 10% byweight of the liquid.

In controlled release oral solid dosage forms, films or tablets, theratio of polyvinyl pyrrolidone to polymeric alginate in the polymericmixture is from about 5:1 to about 1:3. By selecting different ratios ofpolyvinyl pyrrolidone to polymeric alginate, the dissolution time of thefilm may be controlled. The reported dissolution data illustrating theeffect of the ratio of PVP to polymeric alginate for films are tabulatedin Table 1. Each dissolution time represents the average of sixdeterminations. The subjects placed the film into their mouths eitherbuccal or sublingual and the time to total dissolution was measured.

TABLE 1 Film Characterists - Dissolution Sample Code A B C D E Ratio ofPVP/alginate 5:1 4:1 3:1 1:2 1:3 Average dissolving 4 min 6 min 9 min 17min 26 min time (buccal, 2.5 cm²) Average dissolving 3.5 min   4.5 min  7 min 14 min 17 min time (sublingual, 5 cm²)

The procedure for preparing the films of table 1 is described inExamples 1 and 2. The ratio of PVP to polymeric alginate was adjusted bythe techniques illustrated in Examples 2, 2A, 2B, 3 to 9. In forming thefilm, the polyvinyl pyrrolidone and the polymeric alginate salt aremixed in an aqueous solution and the other materials, including thepharmaceutically active agent and absorption enhancers, used in formingthe dosage form of this invention are mixed into this solution.

The greater molecular weight of the polyvinyl pyrrolidone the greaterwill be the drug release time of the films so produced. This isillustrated in Table 3 and Examples 7 and 8. Example 7 contains aPVP:alginate ratio of 2:1 and 0.1620 grams of PVP K60 with a molecularweight of 337,000 daltons. Example 8 contains a PVP:alginate ratio of2:1 and 0.1620 grams of PVP K30 with a molecular weight of 44,000 to54,000 daltons. Example 7 has a buccal release time of 11 minutes 15seconds and a sublingual release time of 9 minutes 53 seconds. Example 8has a buccal release time of 8 minutes 44 seconds and a sublingualrelease time of 6 minutes 34 seconds. The molecular weights of PVP K60of 337,000 daltons compared to the molecular weight of PVP K30 of 44,000to 54,000 daltons being the only difference between the twoformulations.

In fact, as the ratio of polymeric alginate to polyvinyl pyrrolidone inthe polymeric mixture is increased the release time from the film thatis formed will also increase. By varying the molecular weight ofpolyvinyl pyrrolidone and the ratio of the polyvinyl pyrrolidone to thepolymeric alginate one can obtain a release time of from about 1 minuteto about 1 hour or longer.

Additional polymers may be incorporated into the matrix as releasecontrolling additives. Suitable additional polymers may be selected fromthe group comprising hydroxy propyl methyl cellulose, hydroxy ethylcellulose, hydroxy propyl cellulose and polyethylene glycol and likepolymers. Preferably, hydroxy ethylcellulose can be used to decreasefilm hydrophilicity and increase dissolution time to over 25 minutes forboth buccal and sublingual applications. Hydroxy propyl methylcellulosecan be also included to decrease film hydrophilicity and at the sametime to decrease dissolution time to the range of 1-5 minutes.Formulations illustrating the release controlling effect of additionalpolymers are found in Examples 9 to 13.

The unit dosage form may contain known pharmaceutically acceptableadditives, flavoring agents, surfactants and adjuvants. Conventionalplasticizers such as glycerol may also be present in amounts up to about40%. Specifically examples of release-controlling additives such ashydroxypropyl methylcellulose, hydroxypropyl cellulose, and hydroxyethyl cellulose can be added. Conventional flavors such as peppermintoil, sugar or other natural and artificial sweeteners and natural andartificial flavors may be present in the same form of composition ofthis invention. These additives, flavoring agents, sweeteners,plasticizers, surfactants and adjuvants may be incorporated into thefilm by adding to or mixing them into the aqueous solution which is usedto form the film. Generally it is desired that these agents are presentin the amount of from about 0.1% to about 20%. The controlled releasematrix may contains one or more absorption enhancers present in anamount of from about 0.1% to about 20% based upon the weight of thedosage unit which may be a film or tablet preferably from about 1% toabout 20%.

When the unit dosage form further comprising a nonionic surfactant, thecombined nonionic surfactant and sucrose fatty acid ester have acombined HLB of about 8 to about 17.

The solid oral unit dosage form of this invention can be utilized totransport any desired water soluble pharmaceutically active agent. Asused herein, the term “effective amount” designates the amount of drugor pharmaceutical agent that produces the desired biological or medicalresponse of a patient. In accordance with this invention depending uponthe pharmaceutical agent that is administered and the desired biologicalor medical response of a patient desired by the physician, the effectiveamount will vary. In general, the amount of a pharmaceutically activeagent conventionally administered in other unit dosage forms can be usedand administered by the unit dosage form of this invention. The dose ofpharmaceutically active agent may be adjusted to take into accountdifferences in absorption due to the different route of administration.The term “selective” as used herein is means that a major portion of thepharmaceutical agent administered passes through the mucosal membranesof the mouth rather than through the gastrointestinal tract.

The preferred pharmaceutical agent for use in the oral unit dosage formof this invention is an agent for treatment or prevention of migraineheadaches in a patient. The amount which is presented in the dosage formof this invention should be that amount which is effective for treatingor preventing a migraine headache. Any conventional water solublepharmaceutical agent for use for treatment or prevention of migraineheadaches can be used in the amounts that they are conventionally usedin other oral dosage forms. The preferred migraine agents for use in theoral unit dosage form of this invention are triptans and theirpharmaceutically acceptable salts and rizatriptan, sumatriptan,zolmitriptan or their pharmaceutically acceptable salts are preferred.These preferred agents are known agents for use in combating migraineheadaches. The specially preferred agent is rizatriptan or itspharmaceutically acceptable salts, most preferable the benzoate salt.

The unit oral dosage of this invention contains a pharmaceuticallyacceptable mucosal penetrating or permeation enhancer. Thesepharmaceutically acceptable mucosal penetrating or permeation enhancersare incorporated into the film or tablet by adding to or mixing theminto the solution which is used to form the film or tablet. Thesepharmaceutically acceptable mucosal penetrating or permeation enhancersare present in the total amount of about 0.5% to about 20%, preferablyabout 1% to about 20%, more preferably about 1% to about 10% and mostpreferably about 2% to about 10% based upon the weight of the dosageform. The preferred pharmaceutically acceptable mucosal penetrating orpermeation enhancers are selected from the esters of sucroseparticularly the C₁₂ to C₂₀ saturated fatty acid esters of sucrose. Whenone or more than one fatty acid ester of sucrose is included in thematrix, that is a film, oral disintegrating tablet, liquid, spray,paste, gel, oral film, lollipop, lozenge, buccal and gingival patch, thecombined HLB of the fatty acid esters of sucrose will have an HLB ofabout 8 to about 16; preferably about 9 to about 16 and most preferablyabout 9.5 to about 16. The preferred fatty acid esters of sucrose areselected from the group consisting of sucrose stearate, sucrosepalmitate, sucrose laurate, sucrose behenate, sucrose oleate and sucroseerucate. Table 2 lists the HLB values for fatty acid esters of sucroseand the monoester content.

TABLE 2 HLB Value of Fatty Acid Esters of Sucrose ESTER Trade Name HLBvalue Mono ester content Sucrose stearate S-070 <1 <1% S-170 1  1% S-2702 10% S-370 3 20% S-370 Fine 3 20% S-570 5 30% S-770 7 40% S-970 9 50%D-1809 S-1170, 11 55% D-1811 S-1570 15 70% D-1815 S-1670 16 75% D-1816Sucrose palmitate p-170 1  1% P-1570 15 70% D-1615 P-1670 16 80% D-1616Sucrose laurate L-195 1  1% L-595 5 30% LWA-1570 15 70% L-1695 16 80%D-1216 Sucrose behenate B-370 3 20% Sucrose oleate O-170 1  1% OWA-157015 70% Sucrose erucate ER-190 1  0% ER-290 2  2% Sucrose ester ofPOS-135 1  0% mixed fatty acids

The hydrophilic-lipophilic balance (HLB) of a surfactant is a measure ofthe degree to which it is hydrophilic or lipophilic, determined bycalculating values for the different regions of the molecule, asdescribed by W. C. Griffin “Classification of Surface-Active Agents by‘HLB,’” Journal of the Society of Cosmetic Chemists 1 (1949): 311. andW. C. Griffin “Calculation of HLB Values of Non-Ionic Surfactants,”Journal of the Society of Cosmetic Chemists 5 (1954): 259. Other methodshave been suggested, notably by J. T. Davies “A quantitative kinetictheory of emulsion type, I. Physical chemistry of the emulsifyingagent,” Gas/Liquid and Liquid/Liquid Interface. Proceedings of theInternational Congress of Surface Activity (1957): 426-438. All threereferences are incorporated herein by reference.

The HLB for a combination of components with differing HLB value is bythe following formula:

${{HLB}\mspace{14mu}{for}\mspace{14mu} a\mspace{14mu}{combination}\mspace{14mu}{of}\mspace{14mu}{components}} = \frac{\sum\limits_{i = 1}^{n}\left( {H_{i} \times A_{i}} \right)}{\sum\limits_{i = 1}^{n}\left( A_{i} \right)}$where H_(i) is the HLB value of individual component and A_(i) is theamount of individual component.

The matrix of a preferred embodiment may further comprise a nonionicsurfactant. Preferred nonionic surfactants may be one or more of apolysorbate and sorbitan fatty acid ester.

The polysorbate useful in the present invention is selected from thegroup consisting of polyoxyethylene (20) sorbitan monolaurate,polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20)sorbitan and polyoxyethylene (20) sorbitan monooleate.

The sorbitan fatty acid ester useful in the present invention isselected from the group consisting of sorbitan monolaurate, sorbitanmonopalmitate, sorbitan monostearate, sorbitan tristearate and sorbitanmonooleate.

The matrix of this invention may further comprise a secondary absorptionenhancer selected from the group consisting of glycerol, ginger oil,cineole and terpenes. Preferred terpines include limonene, cymene,pinene, pellandrene and the like.

The oral unit dosage form of this invention is produced by forming anaqueous solution of the matrix and polyvinyl pyrrolidone and thepolymeric alginate. In preparing the film, the aqueous solutioncontaining polyvinyl pyrrolidone and sodium alginate is mixed withpharmaceutically active ingredient, plasticizers and pharmaceuticallyacceptable additives, flavoring agents, adjuvants. This mixture is thencast into films by coating and drying generally using a coating andcasting machine. Any conventional means of casting the films by means ofthese machines can be utilized in carrying out the procedure for formingthe films. The aqueous mixture containing the polyvinyl pyrrolidone,sodium alginate, pharmaceutically active ingredient, plasticizers aswell as certain desirable pharmaceutically acceptable additives,flavoring agents, adjuvants is coated on a release liner such as apolyester film. Any conventional release liner can be utilized for thispurpose. Generally the release liner has a silicone surface tofacilitate release of the film after drying. After the aqueous solutioncontaining the polymeric mixture of polyvinyl pyrrolidone and alginatepolymer is coated on the surface of the release liner, the coatedrelease liner is heated to a temperature to dry the coated solution andallow the polyvinyl pyrrolidone and the alginate form a polymeric filmwith the pharmaceutically active agent dispersed therein, preferablyuniformly dispersed therein. Generally drying can take place at fromabout 60° to 80° C. or higher depending on thickness of the filmdesired. Drying time can range from 10 minutes for 4 hours. The dryingand formation of polyvinyl pyrrolidone and sodium alginate polymer filmscan be carried out by conventional means. Once the film is dried, thefilm is die-cut into standard sizes and removed from the release linerto produce the oral unit dosage form. Generally for the oral usagedosage in the form of the film has a surface area from about 0.25 cm² toabout 20 cm² and a weight of about 1 mg to about 200 mg, preferably fromabout 1 cm² to about 10 cm² and a weight of about 10 mg to about 200 mgand a thickness of from about 0.1 mm to about 5 mm.

In preparing the orally disintegrating tablet, the fatty acid ester ofsucrose is dissolved in a solvent such as isopropyl alcohol at elevatedtemperature of about 60° C. Certain adjuvants such as flavoring agents,and nonionic surfactants are added to the solution to form solution A.If to be included in the tablet release controlling agents such aspolyvinyl pyrrolidone (PVP) and alginate salt is prepared by dissolvingin water. Fillers and sweeteners such as mannitol and sucrose areblended to become a powder B. In a fluidized-bed granulator, powder B issprayed with solution A and the optional PVP:alginate solution. Themixture is dried until completely dry. The mixture is then passedthrough a 20 mesh screen or similar process to produce a granulation.This granulated PVP is combined with pharmaceutically active agent,preferably a triptan and additional dry ingredients such as theadditional polymers, sweetener, lubricant which have a particle sizeequivalent to being passed through a 60 mesh screen to form the finalgranulation for tableting. Tablets of appropriate size and shape arethen prepared by techniques well know in the pharmaceutical arts. Theformation of tablets that rapidly dissolve in the oral cavity is knownin the art. Such tablets have, for example, been described in U.S. Pat.Nos. 7,431,942; 5,464,632; and 5,026,560 which are incorporated hereinby reference.

Liquid dosage forms are prepared by dissolving the active agent andabsorption enhancer in water. This liquid dosage form contains aneffective amount of the pharmaceutically active agent dissolved therein.This liquid dosage form further comprises one or more fatty acid estersof sucrose as absorption enhancer having a combined HLB of about 8 toabout 16; preferably about 9 to about 16 and more preferably about 9.5to about 16. Conventional flavorants such as peppermint oil, natural andartificial flavorants, sugar or other natural and artificial sweetenersmay be present in the same form of composition of this invention. Theseadditives, flavoring agents, plasticizers and adjuvants may beincorporated into the liquid dosage form by adding to or mixing theminto the aqueous solution. Small amounts of alcohol may be helpful inachieving solution of these components. Generally it is desired thatthese agents are present in the amount of from about 0.1% to about 20%.Flavorant is defined as a substance that gives another substance flavor,altering the characteristics of the solute, causing it to become sweet,sour, tangy, etc. There are three principal types of flavorings used infoods and useful in this invention, under definitions agreed in the E.U.and Australia:

Natural flavouring substances: Flavouring substances obtained from plantor animal raw materials, by physical, microbiological or enzymaticprocesses. They can be either used in their natural state or processedfor human consumption, but cannot contain any nature-identical orartificial flavouring substances.

-   -   Nature-identical flavouring substances: Flavouring substances        that are obtained by synthesis or isolated through chemical        processes, which are chemically identical to flavouring        substances naturally present in products intended for human        consumption. They cannot contain any artificial flavouring        substances.    -   Artificial flavouring substances: Flavouring substances not        identified in a natural product intended for human consumption,        whether or not the product is processed.

Other active agents or medicaments that would benefit from absorption inthe oral cavity, in particular sublingual administration, may beincluded in the present invention. By the terms “active agent” thepresent invention refers to a compound that has a desired therapeutic orphysiological effect once ingested and/or metabolized. The therapeuticeffect may be one which provides the physical relief from a malady(e.g., diminishes pain, acid reflux or other discomfort), has an effecton the brain chemistry of molecules that determine mood and behavior. Ofcourse these are just examples of what is intended by therapeuticeffect. Those of skill in the art will readily recognize that aparticular agent has or is associated with a given therapeutic effect.

The active agent may be any agent that is traditionally used as amedicament and lends itself to being administered through the oralcavity. Such active agents may be vitamins, chemotherapeutics;antimycotics; oral contraceptives, nicotine or nicotine replacementagents, analgesics, muscle relaxants, antihistamines, decongestants,anesthetics, antitussives, diuretics, anti-inflammatories, antibiotics,antivirals, psychotherapeutic agents, anti-diabetic agents, sexualdysfunction agents and cardiovascular agents.

The following classes of drugs and non-limiting examples and theircorresponding salts are applicable for delivery using an orallydissolving film, particular those which can benefit from a fast onsettime or have a low oral bioavailability including:

-   -   Smoking cessation drugs:        -   Nicotine, nicotine polacrilex, nicotine bitartrate,            hydrochloride and nicotine citrate, nicotine maleate or            mixtures thereof other salts nicotine replacement agents    -   Narcotic analgesics:        -   Fentanyl, hydromorphone, morphine, sufentanyl, methadone,            buprenorphine    -   Anesthetic:        -   Lidocaine (xylocalne), provacaine, benzocaine,    -   Antitussives (OTC handbook for cough, cold, asthma):        -   Hexylrescinol, dextromorphine,    -   Normarcotic analgesics such as the nonsteroidal        anti-inflammatory agents (NSAIDS):        -   Acetaminophen, Ibuprofen, ketoprofen, indomethacin, aspirin            (low dose for cardiovascular), naproxen sodium, ketorolac,            diclofenac, meloxicam, piroxicam,    -   Erectile dysfunction:        -   Sildenafil, tadafil, vardenafil    -   Female sexual dysfunction        -   Sildenafil, tadifil, vardenafil    -   Antihistamines: Colds and Allergy:        -   Certrizine HCl, loratadine, chlorcyclizine HCl,            Chlorpheniramine maleate, dextrochlorpheniramine maleate,            dexbrompheniramine mealate, diphenhydramine citrate,            diphenhydramine HCl, doxylamine succinate, phenindamine            tartrate, pheniramine, pyrilamine mealate, triprolidine HCl,            thonzylamine HCl, clemastine fumarate,    -   Cough:        -   Menthol, camphor, dextromethorphan HBr, guaifenesin, codeine            phosphate, codeine    -   Respiratory Disorders        -   Pseudoephedrine HCl, phenylephrine HCl, guaifenesin,            dextromethorphan HBr.    -   Sore Throat:        -   Benzocaine, menthol, dyclonine, phenol    -   Respiratory Disorders:        -   Ephedrine    -   Heartburn and Dyspepsia:        -   Cimetidine, nizatidine, famotidine, ranitidine, omeprazole    -   Antiemetics:        -   Granisetron, ondansetron, etc. AZ-001, AZ-004, Levadex,            Zelrix, VR-147, ROX-828, COL-144, BF-1, diphenhydramine,            scopolamine, and the like    -   Sleep aids:        -   Zolpidem, Eszopiclone (Lunesta), Zalepon (Sonata),            diphenhydramine, doxylamine, benzodiazepines (such as:            Estazolam (ProSom), Flurazepam (Dalmane), Temazepam            (Restoril), Triazolam (Halcion), Ramelteon (Rozerem)    -   Diarrhea:        -   Loperamide, digestive enzymes (lactase) bismuth            subsalicylate    -   Oral Hygiene:        -   Cetylpyridinum chloride, domiphen, thymol, eucalyptol,            methyl salicylate, menthol, stannous fluoride, sodium            fluoride, benzocaine, phenol, docosanol    -   Antagonists of CGRP receptors as described un U.S. Pat. No.        7,534,784 incorporated in its entirety herein by reference.    -   Migrane treatment: triptans/CGRP        -   Rizatriptan, zomitriptan,        -   Telcagepant, BIBN4096 (Olcegepant)            Other drugs where a convenience of dosing without the need            for liquids to enhance compliance can benefit from delivery            in an orally dissolving film such as:    -   Drugs for hormone replacement        -   Estradiol, testosterone    -   Alzheimer's disease: cholinergics/cholinesterase inhibitors

Donezapil, galantamine, rivastigmine, tacrin, memantine, etc. and theirsalts

Caffeine salt compounds such as caffeine citrate, caffeine sodiumbenzoate, caffeine sodium salicylate, which may be more water solubleand less bitter than caffeine, may also benefit from delivery in anorally dissolving film or ODT of the present invention.

The following examples describe embodiments of the present invention ismore detail.

In the Examples, the following are definition of the ingredients used.

-   Polyvinyl pyrrolidone (PVP) K90: M. W.=1000000-1500000    -   K60: M. W.=337000    -   K30: M. W.=44,000-54,000        The average molecular weight of soluble polyvinylpyrrolidone        (PVP) is expressed in terms of K-value in the pharmacopoeias        valid in Europe, Japan and USA. It is calculated from the        relative viscosity in water and always forms a part of the        commercial name.-   Kelvis: Sodium alginate with high viscosity (760 CPS@1% solution),    M.W=134,640-   Methocel K100 (LV): Hydroxypropyl methylcellulose, MW=26000-   Methocel E4M: Hydroxypropyl methycellulose, MW=93000-   Natrosol 250H Hydroxyethylcellulose (HEC) is a high viscosity grade    (1% solution, 1500-2500 cps).-   Manugel LBA: Sodium alginate with low viscosity (o1% solution, 500    cps), M.W=15840-   Polyox WSR 205: High MW (M. W.=600,000) Water Soluble Resin    Polyethylene Glycol

EXAMPLE 1

Base Solution Preparation

To simplify the mixing operation, “base solution” was prepared by mixing20 grams isopropanol, as solubilizer, and 64 grams glycerol, asplasticizer, followed by the addition of 6.4 grams of sucrose ester (HLB11), 2.4 grams sucrose ester (HLB 5), 4 gram Tween 80 and 0.8 grams Span80, as permeation enhancers. The mixture was heated gently to 45-50° C.with mixing. While the solution was still warm, 0.2 gram of ginger oiland 0.08 gram of peppermint oil, as flavors, were added and mixed untiluniform. Upon cooling to room temperature, a white opaque paste wouldform.

EXAMPLE 2

PVP/Alginate Film 3:1

0.90 grams of 20% polyvinylpyrrolidone (PVP K90, M.W.=1.0-1.5×10⁶) inwater, and 3.0 grams of 2.0% high viscosity sodium alginate (Kelvis,viscosity=760 cps@1% solution) in water were mixed until the solutionwas uniform. With mixing these, 0.245 grams of above “base solution”,0.0513 gram rizatriptan benzoate (14.53 mg of Rizatriptan benzoate isequivalent to 10 mg rizatriptan base), and 0.025 gram of aspartame, astaste-masking agent, were added. Ensure minimal air entrapment in thesolution during mixing. The final viscous mixture was then degassed in avacuum chamber until it was air bubble free. This viscous mixture wasnow ready for wet casting into films on the coating/drying machine. Thefilm fabrication procedure is described below.

The film coating/drying machine (Werner Mathis AG) was used to cast thefilms.

Depending on formula, the machine was first heated to a specifictemperature ranging between 40°-80° C. or higher if needed. The wet filmthickness, the gap setting between the doctor knife and the top ofrelease liner surface, was set at 1 mm for buccal application and at 2mm for sublingual application as adjusted by the micrometer dial. Thedegassed viscous mixture was poured from the solution container acrossthe cross section of the stretched release liner that was pulled tightlyto form a smooth flat surface. When ready to coat, the knife was drawnslowly over the coating solution which would spread the solution evenlyto form a uniform thickness film. The casted wet film on the releaseliner was immediately entered into the drying compartment of the machineset at 80° C. Depending on dry film thickness and its application, the0.1 mm film for buccal application, drying time at 80° C. was about 20minutes. The 0.2 mm thickness film for sublingual application, dryingtime would be double or around 40 minutes.

The dried films were then die-cut into 5 cm² size with both 0.1 and 0.2mm thickness. The targeted 0.1 mm film each 5 cm² would weigh around 50mg with 5 mg rizatriptan benzoate. The targeted 0.2 mm film, the same 5cm² would weigh 100 mg and contain 10 mg rizatriptan benzoate.

EXAMPLE 2A

PVP/Alginate Film 4:1

1.20 grams of 20% polyvinylpyrrolidone (PVP K90, M.W.=1.0-1.5×10⁶) inwater, and 3.0 grams of 2.0% high viscosity sodium alginate (Kelvis,viscosity=760 cps@1% solution) in water were mixed until the solutionwas uniform. With mixing these, 0.245 grams of above “base solution”,0.0513 gram rizatriptan benzoate (14.53 mg of rizatriptan benzoate isequivalent to 10 mg rizatriptan base), and 0.025 gram of aspartame, astaste-masking agent, were added. Ensure minimal air entrapment in thesolution during mixing. The final viscous mixture was then degassed in avacuum chamber until it was air bubble free. This viscous mixture wasnow ready for wet casting into films on the coating/drying machine. Thefilm fabrication procedure was as described above.

The targeted 0.1 mm film each 5 cm² would weigh around 50 mg with 5 mgrizatriptan benzoate. The targeted 0.2 mm film, the same 5 cm² wouldweigh 100 mg and contain 10 mg rizatriptan benzoate.

EXAMPLE 2B

PVP/Alginate Film 5:1

1.50 grams of 20% polyvinylpyrrolidone (PVP K90, M.W.=1.0-1.5×10⁶) inwater, and 3.0 grams of 2.0% high viscosity sodium alginate (Kelvis,viscosity=760 cps@1% solution) in water were mixed until the solutionwas uniform. With mixing these, 0.245 grams of above “base solution”,0.0513 gram rizatriptan benzoate (14.53 mg of rizatriptan benzoate isequivalent to 10 mg rizatriptan base), and 0.025 gram of aspartame, astaste-masking agent, were added. Ensure minimal air entrapment in thesolution during mixing. The final viscous mixture was then degassed in avacuum chamber until it was air bubble free. This viscous mixture wasnow ready for wet casting into films on the coating/drying machine. Thefilm fabrication procedure is as described above.

The dried films were then die-cut into 5 cm² size with both 0.1 and 0.2mm thickness. The targeted 0.1 mm film each 5 cm² would weigh around 50mg with 5 mg rizatriptan benzoate. The targeted 0.2 mm film, the same 5cm² would weigh 100 mg and contain 10 mg rizatriptan benzoate.

EXAMPLE 3

PVP/Alginate Film 2:1

0.80 grams of 20% PVP K90 in water and 4.0 grams of 2.0% Kelvis in waterwere mixed together. While still mixing, 0.245 gram of the “basesolution”, 0.0513 gram rizatriptan benzoate and 0.025 grams of aspartamewere added. The resulting viscous mixture was then degassed in a vacuumchamber until it was air bubble free for use in film casting. The filmfabrication procedure was the same as above Example 2.

EXAMPLE 4

PVP/Alginate Film 1:1

0.60 grams 20% PVP K90 in water and 6.0 grams of 2.0% Kelvis in waterwere first mixed together and then with 0.245 gram of “base solution”,0.0513 gram rizatriptan benzoate and 0.025 grams of aspartame. Themixture was mixed until uniform and degassed in a vacuum chamber untilit was bubble free for film casting. The film fabrication procedure wasthe same as above Example 2.

EXAMPLE 5

PVP/Alginate Film 1:2

0.40 grams 20% PVP K90 in water and 8.0 grams of 2.0% Kelvis in waterwere first mixed together and then with 0.2450 gram of “base solution”,0.0513 gram rizatriptan benzoate and 0.0250 grams of aspartame. Themixture was mixed until uniform and degassed in a vacuum chamber untilit was bubble free for film casting. The film fabrication procedure wasthe same as above Example 2.

EXAMPLE 6

PVP/Alginate Film 1:3

0.30 gram of 20% PVP K90 in water and 9.0 grams of 2% Kelvis in waterwere first mixed together and then with 0.245 gram “base solution”,0.0513 gram rizatriptan benzoate and 0.025 grams of aspartame. Thedegassed mixture was then used for film casting. The film fabricationprocedure was the same as above Example 2.

EXAMPLE 7

PVP K60/Alginate Film 2:1

0.46 gram of 35% PVP K60 (MW=337,000) in water and 1.0 grams of 8% lowviscosity sodium alginate (Manugel LBA) in water were first mixedtogether. This was followed by the addition of 0.245 gram “basesolution”, 0.0513 gram rizatriptan benzoate and 0.025 grams ofaspartame. The degassed mixture was then used for film casting. The filmfabrication procedure was the same as above Example 2.

EXAMPLE 8

PVP K30/Alginate Film 2:1

0.27 gram of 60% PVP K30 (MW=44,000-54,000) in water and 1.0 grams of 8%Manugel LBA in water were first mixed together. This was followed by theaddition of 0.245 gram “base solution”, 0.0513 gram rizatriptan benzoateand 0.025 grams of aspartame. The degassed mixture was then used forfilm casting. The film fabrication procedure was the same as aboveExample 2.

EXAMPLE 9

PVP/Alginate & HEC Film 1:1

0.60 gram of 20% PVP K90 in water, 0.75 grams of 8% Manugel LBA inwater, and 3.0 grams of 2% high viscosity hydroxyethylcellulose(Natrosol 250H) in water were first mixing together until it formed auniform solution. This was followed by the addition with mixing 0.245gram “base solution”, 0.0513 gram rizatriptan benzoate and 0.025 gramsof aspartame. The degassed mixture was then used for film casting. Thefilm fabrication procedure was the same as above Example 2.

EXAMPLE 10

High MW PEG/Alginate & HEC Film

2.0 grams of 4% polyethylene glycol (Polyox WSR 205, MW=600000) inwater, 2.7 grams of 2% Natrosol 250H in water and 1.35 grams of 8%Manugel LBA in water were mixed with 0.245 gram “base solution”, 0.0513gram rizatriptan benzoate and 0.025 gram of aspartame. The degassedmixture was then used for film casting. The film fabrication procedurewas the same as above Example 2.

EXAMPLE 11

HPMC/PVP/Alginate Film

1.66 gram of 6% hydroxypropyl methylcellulose (Methocel K100, MW) inwater, 0.5 grams of 20% K90 PVP in water and 0.5 gram of 8% Manugel LBAin water were mixed with 0.245 gram “base solution”, 0.0513 gramrizatriptan benzoate and 0.025 gram of aspartame. The degassed mixturewas then used for film casting. The film fabrication procedure was thesame as above Example 2.

EXAMPLE 12

HPMC/PVP/Alginate Film

0.66 gram of 6% hydroxypropyl methylcellulose (Methocel K100, MW) inwater, 0.60 grams of 20% K90 PVP in water and 1.00 gram of 8% ManugelLBA in water were mixed with 0.245 gram “base solution”, 0.0513 gramrizatriptan benzoate and 0.025 gram of aspartame. The degassed mixturewas then used for film casting. The film fabrication procedure was thesame as above Example 2.

EXAMPLE 13

HPMC/PVP/Alginate Film

0.66 gram of 6% hydroxypropyl methylcellulose (Methocel K100, MW) inwater, 0.80 grams of 20% K90 PVP in water and 0.50 gram of 8% ManugelLBA in water were mixed with 0.245 gram “base solution”, 0.0513 gramrizatriptan benzoate and 0.025 gram of aspartame. The degassed mixturewas then used for film casting. The film fabrication procedure was thesame as above Example 2.

Results for Dissolution in Mouth for Examples 2-13

In-Vivo Retention Study Using Oral Film

2.5 cm² of film having a thickness of 0.02 cm was applied under thetongue to 6 healthy volunteers. Then, the retention time of film in themouth without any swallowing and drinking was measured.

Two sites applied were sublingual and buccal area in the mouth. Eachsite was used for measuring the retention of individual film. Theaverage dissolution time (in minutes) of each Example was shown in thebelow table 3. Also, the appearance and physical characteristics offilms in Examples were also listed in the below table.

TABLE 3 Average Dissolution Time of Films Example 2 3 4 5 6 7 8 Buccal 8min 15 min 16 min 17 min 26 min 11 min 8 min Film 56 sec 68 sec 33 sec31 sec 36 sec 15 sec 44 sec Sublingual 6 min N/A 13 min 14 min 16 min  9min 6 min Film 66 sec 21 sec 34 sec 58 sec 53 sec 34 sec Dried filmlight tan, light tan, light tan, light tan, Opaque translucenttranslucent appearance translucent translucent translucent translucentExample 9 10 11 12 13 Buccal 5 min 2 min 5 min 2 min 2 min 23 sec 35 sec10 sec 25 sec 12 sec Sublingual 4 min 2 min 3 min 2 min 1 min 14 sec 55sec 15 sec 10 sec 55 sec Dried film translucent translucent translucent,translucent, translucent. appearance light straw, light straw lightstraw

The following are manufacturing methods of orally disintegrating tablets(ODT).

Method A (Examples 14, 15, 16, 17, 19, 20, 21 and 22)

-   1. Dissolve 8 g sucrose ester HLB11 (S-1170) and 3 g sucrose ester    HLB5 (S-570) with 20 ml isopropyl alcohol in water bath at 60 C.    Then mix with 5 g Tween-80 and 1 g Span-80.-   2. Mix 2.5 g ginger oil and 1 g peppermint oil with above solution    to become Solution A-   3. Prepare PVP K30 solution by dissolving 5 g with 100 ml deionized    water-   4. Mix 684 g mannitol and 180 g sucrose to become Powder B-   5. In a fludized-bed granulator, spray into Powder B with Solution A    and PVP K30 solutions.-   6. Continue to dry the resulting mixture in the fludized-bed    granulator for 20 minutes until it is totally dried. Pass the dried    granulation through a 20 mesh screen.-   7. Passage 100 g rizatriptan benzoate, CMS-Na 5 g, 0.5 g aspartame    and 5 g magnesium stearate through 60 mesh screen and then mix them    with the above dry granules to yield the final granulation for    tableting.-   8. Use a tablet machine equipped with 9 mm flat-faced punches to    make tablets each weighing 100 mg.    Method B (Example 18)-   1. Dissolve 8 g sucrose ester HLB11 (S-1170) and 3 g sucrose ester    HLB5 (S-570) with 20 ml isopropyl alcohol in water bath at 60 C.    Then mix with 5 g Tween-80 and 1 g Span-80.-   2. Mix 2.5 g ginger oil and 1 g peppermint oil with above solution    to become Solution A-   3. Prepare PVP K30 solution by dissolving 5 g with 100 ml deionized    water-   4. Prepare 684 g mannitol and 180 g sucrose to become Powder B-   5. Add 50 g rizatriptan benzoate to Powder B-   6. Prepare granulation by mixing Solution A and PVP K30 solution to    Powder B.-   7. The wet mass was sieved through a 20 mesh screen and dried at 60    degree C. for 1.5-3 hours. The dried particles were then passed    through a 20 mesh screen to prepare dry granules.-   8. Pass 50 g rizatriptan benzoate, CMS-Na 5 g, 0.5 g Aspartame and 5    g magnesium stearate through 60 mesh screen and then mix them with    the above dry granules.-   9. Use a tablet machine equipped with 9 mm flat-faced punches to    compress the final granulation into tablets each weighing 100 mg.

Table 4 gives the tablet formulations for the ODTs made by the aboveprocedures. Table 5 presents the dissolution times, the time at whichthe ODTs were completely dissolved, in the oral cavity for thesetablets. All tablets were dissolved in the oral cavity in less than 3minutes 30 seconds.

Table 6 gives the dissolution profile for the tablets using the officialUSP procedure using USP apparatus 2 dissolution testing in water at 37°C. and 50 rpm paddle rotation. In USP apparatus 2 dissolution testing,all of the tablets took longer than 5 minutes for complete dissolutionwith some tablets, Examples 14-18, were not completely dissolved at 30minutes. In the USP test, the percent is solution was determined bymeasuring the amount of rizatriptan in solution.

TABLE 4 Formulation of Orally Disintegrating Tablet Examples 14 to 22Example 14 15 16 17 18 19 20 21 22 Rizatriptan benzoate 10 10 10 10 1010 10 20 10 S-1170 0.4 0 0.8 0.8 0.8 0.8 0.8 1.6 S-570 0.2 0.3 0.3 0.30.3 0.3 0.6 Tween 80 1 0.3 0.5 0.5 0.5 0.5 0.5 1 Span 80 0.7 0.05 0.10.1 0.1 0.1 0.1 0.2 Ginger oil 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.5Aspartame 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.08 Peppermint oil 0.100.10 0.10 0.10 0.10 0.10 0.10 0.2 CMC-Na 0.50 0.50 0.50 0.50 0.50 0.500.50 0.50 0.50 PVP K30 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50Mannitol/Sucrose (3:1) 86.41 87.26 88.5 86.41 86.41 186.41 86.41 76.4184.32 Mg Stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Tab weight, mg 100100 100 100 100 200 100 100 100 Thickness (cm) 0.14 0.14 0.14 0.14 0.140.16 0.22 0.14 0.14 Diameter (cm) 0.9 0.9 0.9 0.9 0.9 0.9 0.9 0.9 0.9sum of Surfactant (%) 1.7 0.95 0 1.7 1.7 1.7 1.7 1.7 3.4 Surfactantsystem HLB 10.59 10.72 — 10.72 10.72 10.72 10.72 10.72 10.72

TABLE 5 Dissolution time in oral cavity of ODT Example 14 15 16 17 18 1920 21 22 Oral dissolve 3 min 3 min 3 min 3 min 2 min 2 min 3 min 2 min 3min time (approx. 06 sec 23 sec 07 sec 01 sec 40 sec 46 sec 08 sec 23sec 09 sec min)

TABLE 6 Result of Dissolution Testing for ODT (in water, 37° C., 50 rpm)Example 14 Time % 15 16 17 18 19 20 21 22 Test (min) Dissolved % % % % %% % % Dissolution 2 22.31 45.65 32.30 21.54 23.32 36.06 25.06 11.5324.50 5 44.38 77.61 77.08 54.98 58.60 64.66 42.87 34.95 48.81 8 60.7181.62 76.90 77.73 89.47 98.40 69.72 60.04 74.46 15 65.86 79.94 84.0687.17 96.17 117.80 76.63 67.39 82.64 30 78.94 81.58 81.29 91.93 94.08117.77 95.97 68.22 100.52

Pharmacokinetic Study Using Liquid Dosage Formulations

Each of the solutions described in Table 7 were given to a group of sixadults by the protocol given in Table 8. Blood levels of rizatriptanwere measured a selected intervals by a liquid chromatographic massspectroscopy procedure. Samples MG100, MG050 and MG033 did not containfatty acid esters of sucrose. MG033A contained 0.7% fatty acid esters ofsucrose having a combined HLB of 6.71. MG033B contained 0.7% fatty acidesters of sucrose having a combined HLB of 10.71. MG033C contained 0.7%fatty acid esters of sucrose having a combined HLB of 9.36 and alsocontained surfactants Span 80 and Tween 80 as well as ginger oil whichinherently contains a small amount of cineole.

The data contained in Table 9 and graphically illustrated in FIGS. 1 and2, demonstrate that the concentration of rizatriptan in plasma ishighest from liquid dosage forms containing rizatriptan and one or morefatty acid esters of sucrose having a combined HLB of about 8 to about16. MG033A-C have the same amount of rizatriptan as active ingredientand identical doses of each was administered. The Cmax is higher forinventive solutions MG033B and MG033C compared to the control MG033 (noabsorption enhanser) and MG033A (With absorption enhanser and an HLB of6.71). Time post dose to maximum blood concentration of rizatriptan(T_(max)) is much shorter for MG033C than for MG033 and Mg033A. Areaunder the curve (AUC) values for the invention solutions MG033B andMG033C are much larger that those of MG033 and MG033A. Area under thecurve for inventive compositions MG033B and C is significantly greaterthan the AUC for MG100 (no absorption enhanser) which contains threetimes the amount of rizatriptan than the inventive compositions. The AUCfor the tablets (table 9) for the commercial ODTs and the swollabletablet is less than the inventive formula MG033A abd MG033B. This isparticularly remarkable in that the rizatriptan base dose for the twotablet formulations is 10 mg whereas the dose for MG033A and Mg033B is6.88 mg rizatriptan base. It was unexpectedly found that dosing orreleasing active agent over a period of time resulted in higher peak andAUC plasma levels. The preferred method of administering active agentwould be with release over a period of time. A preferred method oftreatment releases the active agent over a period of time from about0.25 minutes to about 15 minutes. A more preferred method of treatmentreleases the active agent over a period of time from about 0.5 minutesto about 10 minutes. It is believed that at least a fraction of 1% to80% or greater of the drug (F1) is delivered to and absorbed by the oralmucosa and absorbed systemically and a second fraction of greater than1% to 80% is delivered to and absorbed along the continuous length ofthe esophagus and gastrointestinal tract (GIT). Where the first fraction(F1) results in a rapid onset of action and improved bioavailability.Where the second fraction (F2) results in a longer duration of actionand improved bioavailability. Where the combined F1 and F2 results inimproved bioavailability as seen in the studies.

TABLE 7 Liquid Dosage formulations Groups Group A Group B Ex 23 Ex 24 Ex25 Ex 26 Ex 27 Ex 28 MG100 MG050 MG033 MG033A MG033B MG033C Ingredients% % % % % % Rizatriptan 4.0 2.0 1.333 1.333 1.333 1.333 benzoate S-1170— — — 0.20 0.60 0.80 (HLB 11) S-970 — — — — 0.10 — (HLB 9) S-570 — — —0.50 — 0.30 (HLB 5) Tween 80 — — — — — 0.50 (HLB 15) Span 80 — — — — —0.10 (HLB 4.3) Ginger oil — — — — — 0.25 Ethanol — — — 5.00 5.00 5.00Glyceri — — — 5.00 5.00 5.00 Aspartame — — — 0.02 0.02 0.02 peppermintoil 0.10 0.10 0.10 Deionized Water QS QS QS QS QS QS 100 ml 100 ml 100ml 100 ml 100 ml 100 ml HLB (sum) for 6.71 (0.7) 10.71 (0.7)  9.36 (0.7)sucrose esters HLB (sum) for 6.71 (0.7) 10.71 (0.7) 10.72 (1.7) allenhancers

TABLE 8 Dosing Protocol Group Formulation Dose Administration A MG1000.025 ml 10 min (1 mg/min) MG050 per every 20 min (0.5 mg/min) MG033minute 30 min (0.33 mg/min) B MG033A 0.025 ml 30 min (0.33 mg/min)MG033B per every MG033C minute Total rizatriptan base administered toeach subject in Group A and Group B of table 8 was 6.88 mg.

TABLE 9 Pharmacokinetic Parameters Pharmacokinetic Parameters (n = 6 forsolution, n = 27 for oral) C_(max) T_(max) T_(1/2) AUC₀₋₂ AUC_(0-∞) TestFormula (ng/ml) (hr) (hr) (ng/ml * hr) (ng/ml * hr) Group MG100 23.221.25 2.59 47.15 82.89 A MG050 14.61 1.71 2.52 28.91 57.78 MG033 18.881.42 3.09 18.91 73.24 Group MG033A 17.24 1.92 3.60 16.86 69.92 B MG033B27.08 2.08 2.52 24.82 97.12 MG033C 38.63 1.63 2.00 36.79 132.33 Oral *ODTs 20.94 1.58 N/A 18.83 66.13 (10 mg) Tablet 27.29 0.84 N/A 30.0369.88 * Adapted from Swan etal, J Clin Pharmacol 2006; 46: 172-178 whichis incorporated herein by reference.

A randomized, single-dose, three-period crossover, single-center studyin human designed to compare the pharmacokinetic profiles of six (6)different Rizatriptan ODF formulations administered under the sublingualroute. All the ODF contained 14.53 mg of rizatriptan benzoate(equivalent to 10 mg rizatriptan), while varying in their ODF filmdesigns. A total of eighteen (18) healthy female subjects were recruitedinto the study. The subjects were randomly assigned into either Group Aor Group B, with nine (9) subjects in each group. In each of the threedosing periods, every subject received one (1) of the three (3)different Rizatriptan ODF prototypes: Example 29, Example 30 and Example31 for Group A subjects, and Example 32, Example 33 and Example 34 forGroup B subjects. The sequence of the three (3) formulations given wasarranged in accordance with a randomization scheme. The washout periodbetween each dosing period was 72 hours.

Prior to dosing, all subjects were fasting over night or for at least 8hours, and were further fasting for additional 4 hours post-dosing.Within 2 hours before and 2 hours after the dosing, the study subjectswere refrained from water drinking. The subjects were required not totake caffeine-containing beverage or food at least 3 days prior to thestudy and during the entire study period. Standard meals were providedto the subjects during the day of dosing in each period.

All Rizatriptan ODF prototypes for use in this pharmacokinetic (PK)study were manufactured and supplied in accordance with the guidelinesof Good Manufacturing Practice (GMP).

The six (6) study supply samples, designated as Example 29, Example 30,Example 31, Example 32, Example 33 and Example 34, were all prepared tocontain 14.53 mg of rizatriptan benzoate (equivalent to o10 mgrizatriptan). These ODF formulations, however, were formulated tocomprise different film forming components and film texture designs.Study supply samples of Example 30, Example 31, Example 32 and Example33, which consisted of 10% rizatriptan benzoate, were prepared in twoidentical sheets of the ODF film in a size of 5 cm² per sheet or 10 cm²in total (145 mg as the total weight). Example 29 (14.5% rizatriptanbenzoate) was also prepared in two (2) sheets of the ODF film in a sizeof 3.45 cm² per sheet or 6.9 cm² in total (100 mg in weight). Example 34(14.5% rizatriptan benzoate) was made in one single sheet of the ODFfilm in a size of 5 cm² (100 mg in weight). The formulating compositionsand sizes of the six (6) ODF formulations are shown in Tables o10 and11.

TABLE 10 Formulations of Rizatriptan Orally Disintegrated Films (ODFs)ODF Example 29 Example 30 Example 31 Targeted Film Size: 100 mg/6.9cm{circumflex over ( )}2 145 mg/10 cm{circumflex over ( )}2 145 mg/10cm{circumflex over ( )}2 Ingredients mg mg mg Rizatriptan 14.50 14.5314.53 Benzoate Pullulan 69.29 109.61 110.34 Locust bean gum 0.00 0.000.00 PVP-K90 0.00 0.00 0.00 Na Alginate 0.00 0.00 0.00 (Manugel)Sucralose 1.00 1.45 1.45 Glycerol 8.00 11.62 11.62 S1170 4.00 4.36 4.36Tween 80 2.00 2.18 2.18 Span 80 0.40 0.36 0.36 Peppermint oil 0.30 0.440.44 Menthol 0.50 0.73 0 FD &C Green #3 0.0100 0.0145 0.0145 Film Weight(mg) 100.00 145.30 145.30

TABLE 11 Formulations of Rizatriptan Orally Disintegrated Films ODFExample 32 Example 33 Example 34 Targeted Film Size: 145 mg/10cm{circumflex over ( )}2 145 mg/10 cm{circumflex over ( )}2 100 mg/5cm{circumflex over ( )}2 Ingredients mg mg mg Rizatriptan Benzoate 14.514.53 14.54 Pullulan 108.9 0.00 34.25 Locust bean gum 0.73 0.00 0.00PVP-K90 0.00 86.87 0.00 Na Alginate (Manugel) 0.00 22.74 35.00 Sucralose1.45 1.45 1.00 Glycerol 11.62 11.62 8.00 S1170 4.36 4.36 4.00 Tween 802.18 2.18 2.00 Span 80 0.36 0.36 0.40 Peppermint oil 0.44 0.44 0.30Menthol 0.73 0.73 0.50 FD &C Green #3 0.0145 0.0145 0.01 Film Weight(mg) 145.3 145.30 100.00

Dosage and Administration

All study samples of the ODF prototypes were administered to the studysubjects as single dose applications to the sublingual area. The ODFsamples of Examples 29 to 33 were administered by stacking two sheets ofthe ODF film together. Example 34 ODF was applied as one single sheet.Subjects administered the ODF sublingually without water, and were notallowed for water drinking within 2 hours before and 2 hours after thedosing. During the drug administration, all subjects were asked toexercise their best effort to keep the ODF film remained under thetongue and avoid licking the film, and not to swallow saliva until thefilm was dissolved.

Blood Sampling and Pharmacokientic Analyses

Collection of Biological Samples

During each study period, 5 ml of whole blood samples were collected atdesignated time: 0 (pre-dose), 15, 30 and 45 minutes, 1, 1.33, 1.67, 2,3, 4, 6, 8 and 12 hours after dosing. The sampling time might be variedwithin ±2 minutes at the above mentioned time points. Blood samples werestored in an ice-water bath after collection. Within 5 minutes aftersampling, the blood samples were centrifuged at 3,000 g for 8 minutes.Each of the resultant plasma samples was separated into two portions,one was used for drug concentration assay and the other was stored under−20° C.

Pharmacokinetic Parameters

Plasma levels of rizatriptan were determined using a validated LC/MS-MSbio-analytical method.

The pharmacokinetic parameters analyzed in this study included:AUC_(0-1h), AUC_(0-2h), T_(max), C_(max), T_(1/2), AUC_(0-t), andAUC_(0-∞) for all the six (6) formulations. With reference to a previousPK study on Maxalt® ODT,⁷ the study endpoints of the pharmacokineticanalyses in this study were divided into three (3) types: (1)Primary—AUC_(0-1h) and AUC_(0-2h), (2) Secondary—T_(max), and (3)Exploratory—C_(max) and AUC_(0-∞).

Statistical Analyses

Parameters of C_(max) and AUCs (including AUC₀₋₁, AUC_(0-2h) andAUC_(0-t) and AUC_(0-∞)) were reported in geometric mean values and wereanalyzed with analyses of variances (ANOVA) after being transformed to alogarithmic scale for pair-wise comparisons between the formulations.Both T_(max) and T_(1/2) were reported in mean and median values.Pair-wise comparisons of median T_(max), or T_(1/2), between studyprototypes were performed using a Wilcoxon signed rank test.Pharmacokinetic parameters were analyzed using the DAS Version 2.0software and statistical analyses were performed using SAS 9.13.

Mouth Residence Time

The mouth residence time of the ODF formulations in each application wasobserved and reported by the study subjects. The mouth residence timemeasured the time of the film to be completely dissolved in thesublingual area. The complete dissolution of the film had to be verifiedby investigator, who confirmed that there were no noticeable gel-likeparticles of the dissolved film remaining in the sublingual andsurrounding area. Mean mouth residence time values between ODFformulations were compared using the student t-test.

Taste

The tastes of the ODF formulations were also assessed in this study.Subjects were required to score the degree of sweetness or bitterness ofthe study film according to a 10-point scale and to report any tastesthey felt from the drug administered. The 10-point scale was from 1 to10 including, 1=very bitter, 2=moderately bitter, 3=bitter, 4=somewhatbitter, 5=average, very little bitter, 6=average, very little sweet,7=somewhat sweet, 8=sweet, 9=moderately sweet, and 10=very sweet.Individual taste evaluation results were tabulated and the mean tastescores between prototypes were compared using the student t-test.

Pharmacokinetics

The endpoints of this pharmacokinetic study are summarized in Table 12.All ODF Examples 29 to 34 showed drug concentration profiles withconsiderably improved absorption of rizatriptan, and exhibited muchhigher values of AUC_(0-1h), AUC_(0-2h) and AUC_(0-∞) when compared withthose reported for Maxalt® ODT. The geometric mean AUC_(0-2h) values ofthe ODF formulations were 2 to 2.5 folds of that of the Maxalt® ODT. Theresults also indicated that ODF formulations exhibited a fast absorptionof rizatriptan after sublingual administration. Among the six (6) studyprototypes, Example 30 showed the highest AUC_(0-1h) and AUC_(0-2h)values, the designated primary endpoints.

By analyzing the plasma profiles observed in individual subjects, it wasinteresting to find that there were two (2) absorption peaks in most ofthe administrations of the ODF formulations (76%, 41/54). Thedouble-peak plasma profile of the ODF was primarily attributable to thetwo (2) compartmental absorptions of rizatriptan through i) theoral/sublingual cavity and ii) the gastrointestinal tract. For Examples29 to 34, the median occurrence time of the first peaks (herein definedas T_(max)−1) was 0.75 to 1 hour and that of the second peak (hereindefined as T_(max)−2) was 1.8 to 3 hours (Table 12) in the subjects withdouble-peak profile.

TABLE 12 The Study Endpoints of Pharmacokinetic Parameters Observed forNAL1606 ODF Prototypes Example Example Example Example Example ExampleMaxalt ® End Point 29 30 31 32 33 34 ODT Primary Geometric mean(ng/ml-hr) AUC_(0-1 h 0-1 h) 10.63 13.28 12.29 11.14 10.67 9.11 2.92AUC_(0-1 h 0-2 h) 44.70 46.03 38.02 36.75 37.04 36.41 18.83 SecondaryT_(max(h)) Median 1.67 2.00 2.00 2.00 1.67 2.00 2.92 Mean 1.67 1.89 2.012.11 1.53 2.37 18.83 T_(max-1(h))* Median 0.75 1.00 0.88 1.00 1.00 0.881.33 Mean 0.88 0.79 0.93 1.08 1.18 0.94 1.58 T_(max-2(h))* Median 2.002.00 3.00 2.50 1.84 3.00 Mean 2.05 2.00 2.58 2.46 2.28 2.72 ExploratoryGeometric Mean AUC_(0-1 h 0-∞ (ng/ml-hr)) 180.96 158.40 149.70 132.75123.99 150.22 66.13 C_(Max) (ng/ml-hr) 45.22 39.12 36.05 32.50 30.8132.24 20.94 C_(Max) ⁻¹ (ng/ml-hr) 39.00 35.38 25.93 24.95 30.98 26.47C_(Max) ⁻²(ng/ml-hr)* 43.52 38.08 33.66 28.98 28.95 30.97 *Subjects N =6, 7 or 8 for T_(max)−1, T_(max)−2, C_(max)−1 and C_(max)−2 calculations**Data from Swan S (2006)

In all the subjects, all Examples 29 to 34 reached a mean plasma levelof rizatriptan higher than 10 ng/ml at 0.5 hour, and reachedapproximately 20 ng/ml or higher at 0.75 hour. The mean plasma levelsmaintained in the range of 24 to 35 ng/ml during 1 to 2 hours, and keptwithin the range of 19 to 32 ng/ml during 3 to 4 hours, then declined toapproximate 10 ng/ml at 6 hours (FIG. 3). It can be seen that bothExamples 29 and 30 reached plasma rizatriptan levels at 30 ng/ml orabove throughout the time from 1 to 3 hours. The results suggests thatthe ODF would be able to exhibit an onset of pain relief in as early as30 to 45 minutes, and could offer a prolonged therapeutic action of atleast 4 to 6 hours after a single dose administration. In other words,the ODF may provide a longer duration in efficacy action in comparisonto the Maxalt® ODT.

Primary Endpoints: Area-Under-Curve—AUC_(0-1h) and AUC_(0-2h)

Among the six (6) ODF formulations, Example 30 showed the highestgeometric mean AUC_(0-1h) value (13.28 ng/ml·h) and geometric meanAUC_(0-2h) value (46.03 ng/ml·h). For the other five (5) ODF prototypes,the AUC_(0-1h) ranged from 9.11 to 12.29 ng/ml·h and the AUC_(0-2h)ranged from 36.41 to 44.70 ng/ml·h (Table 12). There were nostatistically significant differences in AUC_(0-1h) and AUC_(0-2h) inpair-wise comparisons between all of the prototypes (p>0.05). However,both the AUC_(0-1h) and AUC_(0-2h) values of all six (6) ODFformulations were considerably higher than those, 2.92 ng/ml·h and 18.83ng/ml·h, respectively, reported for the Maxalt® ODT in the literature.As described by Swan in the 2006 report on the pharmacokinetics ofMaxalt®,⁷ the AUC values up to specific time points near T_(max)(AUC_(01-1h) and AUC_(0-2h)) would be more meaningful surrogates thanthe T_(max) itself to evaluate the rate of absorption. The results onthe AUC values observed in the first two hours of the ODF formulationsdemonstrated that it could provide faster onset, as well as improvedbioavailability of rizatriptan, compared with Maxalt® ODT.

Secondary Endpoints: T_(max), T_(max)−1, and T_(max)−2

The median T_(max) values of the ODF formulations were 1.67 hours forExample 29 and Example 32, and 2 hours for Examples 30, 31, 32 and 34,(Table 12). The median T_(max) values were comparable to that reportedin the prescribing information of Maxalt® ODT (1.6 to 2.5 hours).However, as discussed earlier, “double-peak” plasma profiles (FIG. 1)were observed in most of the cases with sublingual administration ofODF. For the analyses, subjects with double-peak in their plasmaprofiles were identified, and the respective time values to achieve thetwo peaks (T_(max)−1 for the first peak and T_(max)−2 for the secondpeak) and the corresponding maximum peak concentrations (C_(max)−1 andC_(max)−2, respectively) were analyzed (Table 11.6.1 and 11.6.2). Thefirst peaks usually occurred within the first hour post dosing, with amedian T_(max)−1 value from 0.75 hr to 1 hour among these prototypes.The second peak was, in general, seen 1 to 2 hours following the firstpeak, showing a median T_(max)−2 value in a range of 1.8 to 3 hours. Asthe first peaks showed peak concentration values (C_(max)−1) in a rangeof 25 to 39 ng/ml, which were the plasma levels considered as highenough to produce therapeutic effects, therefore, the T_(max)−1 values(0.75 to 1 hour) observed should also be considered of clinicalsignificance. The results observed for the early T_(max)−1 valuescollaborated with the results of significantly high AUC_(0-1h) andAUC_(0-2h) values discussed previously, thereby strongly supporting thefast onset profile of the ODF. There were no significant differences inmedian T_(max) comparisons between these prototypes based on thestatistical analyses (p>0.05) (Table 11.12)

Exploratory Endpoints: AUC_(0-∞), C_(max), C_(max)−1, and C_(max)−2

As outlined in Table 12, the geometric means of the AUC_(0-∞)valuesreported for the ODF were ranging from the least of 123.99 ng/ml·h(NAL1606-205) to the largest of 180.96 ng/ml·h (Example 29). TheAUC_(0-∞)values were more than double when compared with theAUC_(0-∞)value of 66.13 ng/ml·h reported for the Maxalt® ODT. Theresults indicated that ODF demonstrated significantly improvedbioavailability of rizatriptan through an enhanced absorption of thedrug compared with Maxalt® ODT. The geometric mean C_(max) values of ODFformulations showed a range from 30.81 ng/ml (Example 33) to 45.22 ng/ml(Example 29). The C_(max)−1 values, the maximum concentrations of thefirst peak, were reported in a range from 24.95 ng/ml (Example 32) to39.00 ng/ml (Example 29). The C_(max)−2 values, the maximumconcentration of the second peak, were slightly higher than C_(max)−1,ranging from 28.95 ng/ml (NAL1606-205) to 43.52 ng/ml (Example 29).Example 29 showed the highest C_(max), C_(max)−1, and C_(max)−2 amongthe six (6) study formulations. There were statistically significantdifferences in both the AUC_(0-∞) and the C_(max) values between Example29 and Example 33 (each p<0.05), while the differences wereinsignificant in other pair-wise statistical comparisons of theparameters between other prototypes.

Other Pharmacokinetic Parameters

The mean T_(1/2) ranged from 1.77 hour (Example 32) to 2 hour (Example29). The ranking of AUC_(0-t) values among the six (6) ODT formulationswas in the same order as that observed for the values of the AUC_(0-∞).

Mouth Residence Time

Mouth residence times of the ODF formulations after sublingualadministration were assessed in this study. The mouth residence timerefers to the time required for full and complete dissolution of the ODFin the oral cavity. Full and complete dissolution of the ODF is definedas no noticeable gel-like particles of the dissolved film remaining inthe oral cavity, rather than simply a breakdown of the film sheet.Usually it may take approximate 1 to 2 minutes to have the whole pieceof ODF disintegrated in the mouth after sublingual application, but itwould take longer time to see its complete dissolution. In this study,the mean mouth residence times of the ODF ranged from 5.2±1.5 minutes(Example 29) to 8.1±1.1 minutes (Example 33). As a whole, the mouthresidence time among all the dosing administrations (n=54) was, inaverage, 6.6 minutes (Max.10.5 min; Min. 3 min).

In the previously reported pharmacokinetic study for liquid formulationsTables 7, 8 and 9 above, it was concluded that a mouth residence time ofa few minutes up to 10 minutes, rather than a rapid, instant dissolving,would be required for producing faster onset and improved absorption ofthe drug. The results of this study further verified the findings. Asmaller ODF film in the case of Example 29 and a single ODF film in thecase of Example 34 showed relatively faster dissolution in mouth, bothhaving a mean mouth residence time significantly different from that ofExample 33 (p<0.05). All other ODF comparisons in mouth residence timedid not show statistically significant difference (p>0.05).

Taste Evaluation

The tastes of the ODF formulations were evaluated according to a10-point scale of bitterness/sweetness, which was scored from 1 (verybitter) to o10 (very sweet). The results showed a range of mean tastescore from 4.9±1.9 (Example 34) to 6.7±1.7 (Example 32) but nostatistical differences between prototypes. As a whole, among all thedosing administrations (n=54), 76% of the subjects reported a score from5 to 10, representing average to sweet tastes of the ODF formulations.For the 10% loading formulations, i.e. Examples 30, 31, 32 and 33, thepercentage of subjects having average to sweet tastes increased to 83%.

The formulations of this study contained peppermint and menthol as theflavoring agents. The taste of the ODF can be variable, by modifying thetypes of flavors used in the formulation.

Physical dimensions for examples 35 to 46.

-   Example 35: NAL1606-211, size 2 cm×5 cm, thickness 80-120 μm, weight    145.3 mg.-   Example 36: lot 103-6, size 2 cm×1.8 cm, thickness 80-120 μm, weight    40.0 mg.-   Example 37: lot 103-11, size 2 cm×1.8 cm, thickness 80-120 μm,    weight 40.0 mg.-   Example 38: lot 103-22, size 2 cm×2 cm, thickness 80-120 μm, weight    50.0 mg.-   Example 39: NAL1619, 3 cm×4.5 cm, thickness 80-120 μm, weight 200    mg.-   Example 40: NAL6011-Cetirizine, 2 cm×3.5 cm, thickness 80-120 μm,    weight 100 mg.-   Example 41. NAL1610-Zolmitriptan, 2 cm×2 cm, thickness 80-120 μm,    weight 50.0 mg.-   Example 42: NAL1622-Sumatriptan, 3 cm×4.5 cm, thickness 80-120 μm,    weight 200 mg.-   Example 43: NAL1617K-Ketoprofen, 2 cm×5 cm, thickness 80-120 μm,    weight 150 mg.

The above thickness and dimension are approximately measured valueaverages. The following three examples are predicated values.

-   (Predicted) Example 44. NAL8817-Donepezil, 2 cm×2 cm, thickness    80-120 μm, weight 50.0 mg.-   (Predicted) Example 45. NAL1239-Fentanyl, 2 cm×1.2 cm, thickness    80-120 μm, weight 31 mg.-   Example 46. NAL1606-high viscosity: 2 cm×5 cm, thickness 80-120 μm,    weight 145.3 mg.

EXAMPLE 35 NAL1606 Rizatriptan Benzoate ODF

TABLE 13 Formulation NAL1606-211 ODF NAL1606-211 Size/Thickness 2 cm × 5cm/100 μm Weight (mg) 145.3 mg Working Dry Dry Wet Workable Wet FilmFilm Formula Formula Formula Ingredients mg w/w % mg mg mg % 100 gramRizatriptan 14.53  10% 14.53 14.53 14.53 2.52% 2.52 Benzoate Pullulan102.49 70.54%  102.49 512 mg 512 89.03% 89.03 20% Solution PurifiedWater* 0.00 0.00% 412.87 0.00 Sucralose 1.74 1.20% 1.74 1.74 1.74 0.30%0.30 Alcohol* 0.00 0.00% 17.44 17.44 Glycerin 17.44 12.00%  17.44 17.44Sucrose Fatty 4.36 3.00% 4.36 4.36 Acid Esters D- 1811 Polysorbate 802.18 1.50% 2.18 2.18 (Tween 80) Sorbitan 0.36 0.25% 0.36 0.36 43.957.64% 7.64 g of Monooleate Intermediate (Span 80) mixture Cherry Flavor0.73 0.50% 0.73 0.73 Spearmint Oil 0.36 0.25% 0.36 0.36 Peppermint Oil0.36 0.25% 0.36 0.36 Menthol 0.73 0.50% 0.73 0.73 FD &C Green 0.01450.01% 0.0145 2.9 mg 2.906 0.50% 0.50 #3 0.5% solution Film Weight 145.30100.00%  575.61 575.61 100.00% 100

TABLE 14 Premix A: Intermediate Ingredients Weight(g) Ethanol 6 Glycerin6 Sucrose Fatty Acid Esters D-1811 1.5 Polysorbate 80 (Tween 80) 0.75Sorbitan Monooleate (Span 80) 0.125 Cherry Flavor 0.25 Spearmint Oil0.125 Peppermint Oil 0.125 Menthol 0.25

Manufacturing Procedure for NAL1606 Rizatriptan ODF

(Dosage Strength: 10 mg):

-   -   1. Premix A (Intermediate Mix): Dissolve and mix well sucrose        fatty acid esters D1811, glycerin, Tween 80, Span 80, cherry        flavor, spearmint oil, peppermint oil, menthol together with        ethanol at 60° C.    -   2. Premix B (20% of pullulan solution): Dissolve pullulan        (17.97 g) in water (72.11 g) and mix well at 60° C.    -   3. Premix C (0.5% of FD & C Green #3): Dissolve 0.1 g of FD&C #3        into 19.9 g of water, mix well.    -   4. Solution D: Add rizatriptan benzoate into Premix B, mix well.    -   5. Solution E: Add sucralose into Solution D, mix well.    -   6. Solution F: Add Premix A into Solution E, mix well at about        60° C.    -   7. Coating Solution: Add 0.5 g of Premix C into Solution F, mix        well at about 60° C.    -   8. After mixing, deaerate the Coating Solution thoroughly.

Film Forming Process

-   -   1. The Werner Mathis AG coating machine was used to cast the        films. First the machine was heated to 80° C. The wet film        thickness, the gap setting between the doctor knife and the top        of a PET film surface, was set between about 0.7 mm to about 1        mm.    -   2. Mount the PET film to form a smooth flat surface.    -   3. The degassed coating solution was poured from the solution        container across the cross section of the PET film.    -   4. When ready to coat, the knife was drawn slowly over the        coating solution which would spread the solution evenly to form        a uniform thickness film.    -   5. The casted wet film on the PET film was immediately entered        the drying compartment of the machine set at about 80° C. for 20        minutes.    -   6. The dried films were then cut into small films in a size of 2        cm by 5 cm.    -   7. For PK (Pharmacokinetic) studies, the 2 cm by 5 cm film is        further cut into 2 equal pieces of 2 cm by 2.5 cm each.

EXAMPLE 36 NAL2762 Nicotine ODF

TABLE 15 Formulations NAL2762-102 ODF NAL2762-102 Lot103-6 Dry Film DryFilm Wet Formula Ingredients mg w/w % mg Nicotine base 1.00 2.50% 1.00Sucrose Fatty Acid 2.00 5.00% 2.00 Esters D-1811 Alcohol* 0.00 0.00%17.00 Pullulan 31.18 77.95% 31.18 Purified Water* 0.00 0.00% 132.68Sucralose 0.48 1.20% 0.48 Glycerin 4.00 10.00% 4.00 Polysorbate 80 0.601.50% 0.60 (Tween 80) Sorbitan 0.10 0.25% 0.10 Monooleate (Span 80)Peppermint Oil 0.40 1.00% 0.40 Menthol 0.20 0.50% 0.20 FD&C Yellow #60.040 0.10% 0.040 Film Weight 40.00 100.00% 189.68

EXAMPLE 37 NAL2762 Nicotine ODF

TABLE 16 Formulation NAL2762-103 ODF NAL2762-103 Lot 103-11 Dose (mg-Nicotine) 1.00 mg Total ODF Weight (mg) 40.00 mg Dry Film Dry Film WetFormula Ingredients mg w/w % mg Nicotine base 1.00 2.50% 1.00 AlginicAcid 0.50 1.25% 0.50 Pullulan 29.48 73.70% 29.48 Purified Water* 0.000.00% 134.38 Sucralose 0.48 1.20% 0.48 Solutol H15 1.00 2.50% 1.00Sucrose Fatty 1.00 2.50% 1.00 Acid Esters D-1811 Alcohol* 0.00 0.00%5.20 Glycerin 3.20 8.00% 3.20 Triethyl Citrate 2.00 5.00% 2.00Polysorbate 80 0.60 1.50% 0.60 (Tween 80) Sorbitan 0.10 0.25% 0.10Monooleate (Span 80) Peppermint Oil 0.40 1.00% 0.40 Menthol 0.20 0.50%0.20 FD&C Yellow #6 0.04 0.10% 0.040 Film Weight 40.00 100.00% 179.58

EXAMPLE 38 NAL2762 ODF

TABLE 17 Formulation NAL2762-P01 ODF NAL2762-P01 Lot 103-22 Dose(mg)-Nicotine 1.00 mg Total Weight 50.00 mg Dry Film Dry Film WetFormula Ingredients mg w/w % mg Nicotine 5.00 10.00% 5.00 Polacrilex 20%Pullulan 33.73 67.45% 33.73 Purified Water* 0.00 0.00% 144.85 Sucralose0.60 1.20% 0.60 Glycerin 7.50 15.00% 7.50 Propylene Glycol 0.00 0.00%0.00 Alcohol* 0.00 0.00% 7.50 Sucrose Fatty 1.50 3.00% 1.50 Acid EstersD-1811 Polysorbate 80 0.75 1.50% 0.75 (Tween 80) Sorbitan 0.13 0.25%0.13 Monooleate (Span 80) Peppermint Oil 0.50 1.00% 0.50 Menthol 0.250.50% 0.25 FD&C Yellow #6 0.05 0.10% 0.050 Film Weight 50.00 100.00%202.35

Physical Properties

TABLE 18 Evaluation of physical properties, taste, and in vivodissolution of NAL2762 ODF Examples 36, 37 and 38. Code NAL2762-102NAL2762-103 NAL2762-P01 Lot # 103-6 103-11 103-22 API Nicotine baseNicotine Base Nicotine polacrilex Dose of each ODF (mg nicotine) 1 mg 1mg 1 mg nicotine Physical Overall Acceptability 4 2 2 Attributes Tearresistance 4 2 2 Flexibility 3 3 4 Tensile strength 4 4 1 Elongation 0 02 Rigidity 4 4 2 Film Curved Edges or Wavy 0 2 0 Pencil eraser Tack 0 00 Finger tack 3 1 3 Easy to remove from pouch 4 4 4 Stick to itself 0 00 Organoleptic Sweet 2 3 3 Attributes Bitter 1 0 0 Sour 0 0 0 Salty 0 00 Other Taste Peppermint Peppermint Peppermint Mouth Feel 2 3 3 OverallTaste Evaluation 2 3   2.5 In vivo complete dissolution 3 min 15 sec 2min 59 sec 3 min 06 sec

EXAMPLE 39 NAL1619 (Diclofenac Sodium and Rizatriptan Benzoate) ODF

TABLE 19 Formulation NAL1619: Code Riza-Diclo (NAL1619) Dry Film DryFilm Ingredients mg w/w % Riza Benzoate 5.00 2.50% Diclofenac 20.0010.00% Sodium Pullulan 136.08 68.04% Sucralose 2.40 1.20% Ethanol 0.000.00% Glycerol 24.00 12.00% D1811 6.00 3.00% Tween 80 3.00 1.50% Span 800.50 0.25% Cherry Flavor 1.00 0.50% Spearmint oil 0.50 0.25% Peppermintoil 0.50 0.25% menthol 1.00 0.50% FD &C Green #3 0.02 0.01%

TABLE 20 Dissolution Profile of NAL1619ODF Example 39: Dissolutioncondition: 50 rpm 37 C., paddle over disk Lot 09050601 1 2 3 aveRizatriptan 2 40.5027 38.8877 73.536 50.975467 Benzoate 5 90.709186.0135 106.4637 94.395433 10 116.1855 104.9442 117.6836 112.93777 15119.3446 109.1228 121.9668 116.8114 20 122.356 113.6185 121.0956119.02337 Diclofenac 2 61.7854 55.3473 86.9744 68.0357 Sodium 5 99.868895.9334 109.4492 101.75047 10 116.7546 108.2991 116.3372 113.79697 15116.6002 110.3854 117.6814 114.889 20 118.2711 113.156 118.2983116.57513

EXAMPLE 40 NAL6011-Cetirizine ODF

TABLE 21 NAL6011-101 Formulation ODF NAL6011-101 Size/Thickness 2 cm × 5cm/100 μm Weight (mg) 100 mg Dry Film Dry Film Wet Formula Ingredientsmg w/w % mg Cetirizine HCL 10.00  10% 10.00 Pullulan 69.30 69.30%  69.30Purified Water* 0.00 0.00% 326.95 Sorbitol 5.00 5.00% 5.00 Sucralose1.20 1.20% 1.20 Alcohol* 0.00 0.00% 8.00 Glycerin 8.00 8.00% 8.00Sucrose Fatty 3.00 3.00% 3.00 Acid Esters D-1811 Polysorbate 80 1.501.50% 1.50 (Tween 80) Sorbitan 0.25 0.25% 0.25 Monooleate (Span 80)Peppermint Oil 1.00 1.00% 1.00 Menthol 0.50 0.50% 0.50 FD &C Yellow #60.25 0.25% 0.2500 Film Weight 100.00 100.00%  434.95

TABLE 22 Dissolution Profile of NAL6011 Example 40 Dissolution: Medium:Water, Condition: 50 rpm, 37 C. Paddle over disk. Test Method UV Lot:NAL6011-090581801 Assay 1 2 Ave 9.4202 9.741 9.5807 Min 1 2 3 4 5 6 AveDissolution 2 86.43 87.57 84.45 100.04 82.75 95.78 89.5 2009.5.21- 496.92 100.9 106.27 103.72 96.92 107.12 102 5.22 6 103.44 108.3 111.09109.1 103.15 105.99 106.8 8 109.39 110 102.59 107.12 107.3

EXAMPLE 41 Zolmitriptan ODF NAL1610-Lot103-50

TABLE 23 Formulation NAL1610 Example 41 Code NAL1610 Film Weight 50 mgDry Film Dry Film Wet Formula Ingredients mg w/w % mg Zolmitriptan 2.505.00% 2.50 Pullulan 38.77 77.54% 194 mg of 20% pullulan Sucralose 0.601.20% 0.60 Ethanol 0.00 0.00% 5.00 Glycerol 5.00 10.00% 5.00 D1811 1.503.00% 1.50 Tween 80 0.75 1.50% 0.75 Span 80 0.13 0.25% 0.13 Peppermintoil 0.50 1.00% 0.50 menthol 0.25 0.50% 0.73 FD &C Green #3 0.01 0.01%2.91 mg of 0.5% solution Film Weight 50.00 100.00%

TABLE 24 Physical Property Evaluation of Example 41 NAL1610 ODF: CodeNAL1610 Lot # 103-50 API and Dosage 2.5 mg zolmitriptan/50 mg ODFPhysical Overall 3 Attributes Acceptability Tear resistance 3Flexibility 3 Tensile strength 4 Elongation 0 Rigidity 4 Film Curved 0Edges or Wavy Pencil eraser Tack 0 Finger tack 2 Easy to remove 4 frompouch Stick to itself 0

EXAMPLE 42 NAL1622-Sumatriptan ODF

TABLE 25 Formulation NAL1622 Example 42 Code NAL1622-200 mg Film Weight200 mg Date Dry Film Dry Film Wet Formula Ingredients mg w/w % mgSumatriptan 35.00 17.50% 35.00 succinate¹ Pullulan 130.08 65.04% 650 mgof 20% pullulan in water Sucralose 2.40 1.20% 2.40 Ethanol 0.00 0.00%20.00 Glycerol 20.00 10.00% 20.00 D1811 6.00 3.00% 6.00 Tween 80 3.001.50% 3.00 Span 80 0.50 0.25% 0.50 Peppermint oil 2.00 1.00% 2.00menthol 1.00 0.50% 0.73 FD &C Green #3 0.02 0.01% 2.91 mg of 0.5%solution Film Weight 200.00 100.00% ¹35 mg of sumatriptan succinate isequivalent to 25 mg of sumatriptan base.

TABLE 26 Physical Attributes of NAL1622 Sumatriptan Example 42 ODF: CodeNAL1622 Lot # 103-51 API and Dosage 25 mg sumatriptan/200 mg ODFPhysical Overall 4 Attributes Acceptability Tear resistance 2Flexibility 3 Tensile strength 4 Elongation 0 Rigidity 4 Film Curved 0Edges or Wavy Pencil eraser 1 Tack Finger tack 3 Easy to remove 4 frompouch Stick to itself 0

EXAMPLE 43 NAL1617K Ketoprofen ODF

TABLE 27 Formulation NAL1617K Example 43 ODF CodeNAL1617K-ketoprofen-150 Film Weight/Size 150 mg Date Dry Film Dry FilmWet Formula Ingredients mg w/w % mg Ketoprofen 25.00 16.67% 25.00Pullulan 98.81 65.87% 494 mg of 20% pullulan in water Sucralose 1.801.20% 1.80 Ethanol 0.00 0.00% 15.00 Glycerol 15.00 10.00% 15.00 D18114.50 3.00% 4.50 Tween 80 2.25 1.50% 2.25 Span 80 0.38 0.25% 0.38Peppermint oil 1.50 1.00% 1.50 menthol 0.75 0.50% 0.73 FD &C Green #30.02 0.01% 2.91 mg of 0.5% solution Film Weight 150.00 100.00%

TABLE 28 Physical Property of NAL1617K Example 43 Code NAL1617K Lot #103-54 API and Dosage 25 mg ketoprofen/100 mg ODF Physical Overall 3.5Attributes Acceptability Tear resistance 2 Flexibility 3 Tensilestrength 4 Elongation 0 Rigidity 4 Film Curved 0 Edges or Wavy Pencileraser 0 Tack Finger tack 3 Easy to remove 4 from pouch Stick to itself0

Examples 44-46 illustrate how one would make an ODF for Donepezil,Fentanyl and Rizatriptan benzoate respectively

EXAMPLE 44 NAL8817 Donepezil ODF

TABLE 29 Formulation NAL8817 Donepezil ODF Example 44 Code NAL 8817Donepezil ODF Film Weight/Size 50 mg Date Dry Film Dry Film Wet FormulaIngredients mg w/w % mg donepezil 5.00 10.00% 5.00 hydrochloridePullulan 36.27 72.54% 181 mg of 20% pullulan in water Sucralose 0.601.20% 0.60 Ethanol 0.00 0.00% 5.00 Glycerol 5.00 10.00% 5.00 D1811 1.503.00% 1.50 Tween 80 0.75 1.50% 0.75 Span 80 0.13 0.25% 0.13 Peppermintoil 0.50 1.00% 0.50 menthol 0.25 0.50% 0.73 FD &C Green #3 0.01 0.01%2.91 mg of 0.5% solution Film Weight 50.00 100.00%

EXAMPLE 45 NAL1239 Fentanyl ODF Formulation

Bulk ODF ODF Coating NAL1239 (Dry Film) (Dry Film) Solution NoIngredients (mg) (w/w %) mg 1 Fentanyl Citrate 0.314 1 0.314 2 Pullulan,NF 24.98 79.54 24.98 3 Purified Water, USP* 0.00 0 99.90224 5 Sucralose,GRAS 0.38 1.2 0.38 6 Alcohol, USP* 0.00 0 3.00 7 Glycerin, USP 3.77 123.00 8 Sucrose Fatty Acid 0.94 3 0.75 Esters D-1811, 9 Polysorbate 80,NF 0.47 1.5 0.38 (Tween ® 80) 10 Sorbitan Monooleate, 0.08 0.25 0.06 NF(Span ® 80) 11 Cherry Flavor, 0.16 0.5 0.13 12 Spearmint Oil, 0.08 0.250.06 CDER Listed 13 Peppermint Oil, NF 0.08 0.25 0.06 14 Menthol, USP0.16 0.5 0.13 15 FD &C Green #3, 0.00314 0.01 3.00 CDER Listed FilmWeight 31.4 100.00% 133.45

EXAMPLE 46 Medium/High Viscosity Water-Ethanol Based Formulation

ODF NAL1606-50% Solid Size/Thickness 2 cm × 5 cm/100 μm Weight (mg)145.3 mg Dry Film Dry Film Wet Formula Ingredients mg w/w % mgRizatriptan 14.53  10% 14.53 Benzoate Pullulan 102.49 70.54%  102.49Water 0.00 0.00% 100.00 Ethanol 0.00 0.00% 30.00 Sucralose 1.74 1.20%1.74 Glycerin 17.44 12.00%  17.44 Sucrose Fatty 4.36 3.00% 4.36 AcidEsters D-1811 Polysorbate 80 2.18 1.50% 2.18 (Tween 80) Sorbitan 0.360.25% 0.36 Monooleate (Span 80) Cherry Flavor 0.73 0.50% 0.73 SpearmintOil 0.36 0.25% 0.36 Peppermint Oil 0.36 0.25% 0.36 Menthol 0.73 0.50%0.73 FD &C Green #3 0.0145 0.01% 0.0145 Total 145.30 100.00%  275.30

Preparation of Medium/High Viscosity Formulation

-   -   1. Premix A (Intermediate Mix): Mix sucrose fatty acid esters        D1811, glycerin, Tween 80, Span 80, cherry flavor, spearmint        oil, peppermint oil, menthol together with ethanol at 60° C.    -   2. Premix B: Dissolve pullulan, sucralose and FD&C Green #3 in        water, and mix well at 100° C.    -   3. Solution C: Add rizatriptan benzoate into Premix B, and mix        well.    -   4. Coating Solution D: Combine Premix A and Solution C, mix well        at 100° C.        Method to Produce Orally Dissolving Film Dosage Forms from        Medium/High Viscosity Formulations

The medium/high viscosity Coating Solution D can be further made intoorally dissolvable dosage forms using different methods such asextrusion at room temperature or extrusion at slightly elevatedtemperatures and extrusion particularly through a slot die method bycoating onto a support substrate such as polyester to form ribbons,rods, ovoid and other shapes then further processed by drying at 80 to100° C. and subsequently and cut into unit dosage forms such as films,tablets or lozenges.

Method to Produce Orally Dissolving Dosage Film Forms from HighViscosity Formulations

A solvent less polymer carrier formulation composition can be melted byheating at 80 to 200° C. into a high viscosity flowable formulationwhich can be further made into orally dissolvable dosage forms usingdifferent methods such as extrusion (by using single or twin screws orpumping through a slot die) and formed into ribbons, rods, ovoid andother shapes, then cooled to room temperature and cut into unit dosageforms such as films, tablets or lozenges.

We claim:
 1. A pharmaceutical composition for application to the oralmucosa comprising: a water soluble matrix comprising an effective amountof a pharmaceutically active agent and an absorption enhancer having anHLB of about 8 to about 16, wherein the matrix is a film; the absorptionenhancer is one or more sucrose fatty acid esters; and thepharmaceutically active agent is an agent for the treatment of smokingcessation in a patient and is present in an amount which is effectivefor treating smoking cessation.
 2. The pharmaceutical composition ofclaim 1 wherein the pharmaceutically active agent is a nicotine ornicotine replacement agent or a pharmaceutically acceptable saltthereof.
 3. The pharmaceutical composition of claim 1 wherein thepharmaceutically active agent is selected from the group consisting ofnicotine, nicotine polacrilex, nicotine bitartrate, hydrochloride andnicotine citrate, nicotine maleate and mixtures thereof.
 4. Thepharmaceutical composition of claim 1 further comprising a nonionicsurfactant wherein the combined nonionic surfactant and sucrose fattyacid ester have a combined HLB of about 8 to about
 17. 5. Thepharmaceutical composition of claim 4 wherein the nonionic surfactant isat least one or more of polysorbate and sorbitan fatty acid ester. 6.The pharmaceutical composition of claim 4 further comprising a secondaryabsorption enhancer selected from the group consisting of glycerol,ginger oil, cineole and terpenes.
 7. The pharmaceutical composition ofclaim 5 wherein the polysorbate is selected from the group consisting ofpolyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitanmonopalmitate, polyoxyethylene (20) sorbitan and Polyoxyethylene (20)sorbitan monooleate.
 8. The pharmaceutical composition of claim 5wherein the sorbitan fatty acid ester is selected from the groupconsisting of sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan tristearate and sorbitan monooleate.
 9. Thepharmaceutical composition of claim 1 further comprising a film formingagent selected from pullulan or a polymeric mixture of polyvinylpyrrolidone and a polymeric alginate.
 10. The pharmaceutical compositionof claim 9 wherein the film forming agent is pullulan.
 11. Thepharmaceutical composition of claim 9 wherein the ratio of polyvinylpyrrolidone to polymeric alginate in the polymeric mixture is from about5:1 to about 1:3.
 12. The pharmaceutical composition of claim 9 whereinthe polymeric mixture contains, from about 5% to about 95% by weight ofpolyvinyl pyrrolidone and from about 5% to about 95% by weight of anpolymeric alginate, both of said weights being based on the weight ofsaid polymeric mixture.
 13. The pharmaceutical composition of claim 1wherein said sucrose fatty acid ester is a C12 to C20 saturated fattyacid ester of sucrose.
 14. The pharmaceutical composition of claim 1wherein the sucrose fatty acid esters are selected from the groupconsisting of sucrose stearate, sucrose palmitate, sucrose laurate,sucrose behenate, sucrose oleate and sucrose erucate.
 15. Thepharmaceutical composition of claim 1 wherein said sucrose fatty acidester is a sucrose stearate.
 16. The pharmaceutical composition of claim1 wherein the sucrose fatty acid esters are sucrose fatty acid estershaving a monomer content of from about 20 percent to about 80 percent.17. The pharmaceutical composition of claim 1 wherein said film has asurface area of from 0.25 cm² to 20 cm² and a weight of about 1 mg toabout 200 mg or a surface area of from 1 cm² to 10 cm² about 200 mg anda weight of about 10 mg to 200 mg.
 18. The pharmaceutical composition ofclaim 1 wherein said film contains one or more absorption enhancers inan amount of from about 0.1% by weight to about 20%, by weight of thefilm.
 19. The pharmaceutical composition of claim 1 wherein thepharmaceutical composition dissolves in the oral cavity in about 0.25minutes to about 15 minutes.
 20. The pharmaceutical composition of claim1 wherein the film when placed in the oral cavity will dissolve in about0.25 minutes to about 15 minutes.
 21. The pharmaceutical composition ofclaim 1 wherein the film has a thickness of about 0.01 mm to about 5 mm.22. A method of drug delivery wherein at least a fraction of 1% to 80%or greater of the drug (Fl) is delivered to and absorbed by the oralmucosa and absorbed systemically and a second fraction of greater than1% to 80% is delivered to and absorbed along the continuous length ofthe esophagus and gastrointestinal tract wherein the first fraction (F1)results in a rapid onset of action and improved bioavailability andwherein the second fraction (F2) results in a longer duration of actionand improved bioavailability such that the combined F1 and F2 results inimproved bioavailability, wherein the drug is nicotine or its salt.